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| United States Patent |
6,218,379
|
|
Bohringer
, et al.
|
April 17, 2001
|
Tricyclic carbacephems
Abstract
The present invention is concerned with compounds of formula
##STR1##
where A is a group of formula (b1) or (b2)
##STR2##
where R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents defined herein, and R is as defined herein, together with the
pharmaceutically compatible, readily hydrolyzable esters and salts of
these compounds. These compounds have valuable antibacterial properties.
| Inventors:
|
Bohringer; Markus (Mohlin, CH);
Pflieger; Philippe (Folgensburg, FR)
|
| Assignee:
|
Hoffmann-la Roche Inc. (Nutley, NJ)
|
| Appl. No.:
|
857280 |
| Filed:
|
May 16, 1997 |
Foreign Application Priority Data
| Current U.S. Class: |
514/210.03; 540/205 |
| Intern'l Class: |
C07D 463/16; C07D 463/18; A61K 031/437; A61D 031/04 |
| Field of Search: |
540/205
514/210,210.03
|
References Cited
U.S. Patent Documents
| 5494666 | Feb., 1996 | Bohringer et al. | 514/210.
|
| 5510343 | Apr., 1996 | Charnas et al. | 514/210.
|
| Foreign Patent Documents |
| 508 234 | Oct., 1992 | EP.
| |
| 0548 186 B1 | Jun., 1993 | EP.
| |
| 671 401 | Sep., 1995 | EP.
| |
| WO 92/04353 | Mar., 1992 | WO.
| |
Other References
Hackh's Chemical Dictionary, 3rd edition, p. 853.*
Beilstein Registry 5626344 Printout.*
"Protective Groups in Organic Synthesis", Chapter 5, pp. 152-192 (1981).
|
Primary Examiner: Berch; Mark L
Attorney, Agent or Firm: Johnston; George W., Rocha-Tramaloni; Patricia S., Ebel; Eileen M.
Claims
What is claimed is:
1. A compound of formula I
##STR98##
wherein
R is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl
substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower
alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower
(cyclo)alkanoyl; or lower (cyclo)alkanoyl substituted by halogen, cyano,
carbamoyl-lower alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower
alkylamino, unsubstituted lower (cyclo)alkylsulphonyl; or lower
(cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower
alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino;
unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl,
lower alkoxycarbonyl-lower alkyl, benzyloxy-carbonyl-lower alkyl,
carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure
of the formula
Q--X--CO-- (a1)
or
Q--X--SO.sub.2 -- (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen;
X is a direct bond or a group --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.dbd.CH--, --NH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --CH(NH.sub.2)--,
--CH.sub.2 CH.sub.2 NH--, --C(.dbd.NOCH.sub.3)--, --OCH.sub.2 -- or
--SCH.sub.2 --; and
A is a group of formula (b1) or (b2)
##STR99##
wherein
R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl,
lower alkoxy, aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5
R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6
COO-- in which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl;
R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl,
lower alkenyl or a carboxylic acid protecting group selected from
benzhydryl, p-nitrobenzyl, and p-methoxybenzyl; an unsubstituted
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen; a heterocyclyl which is a 5- or 6-membered
ring optionally containing nitrogen, sulfur and/or oxygen substituted by
lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino,
mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio,
carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower
alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted
benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted
benzyl, lower alkenyl substituted phenyl, --CONR.sup.5 R.sup.6, --CH.sub.2
--CONR.sup.5 R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO--
or R.sup.6 COO-- in which R.sup.5 is hydrogen, lower alkyl or lower
cycloalkyl; R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen,
lower alkyl, lower alkenyl or a carboxylic acid protecting group selected
from benzhydryl, p-nitrobenzyl and p-methoxybenzyl; or a heterocyclyl
which is a 5- or 6-membered ring optionally containing nitrogen, sulfur
and/or oxygen having a phenyl ring fused thereto, the heterocyclyl thereof
being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen,
halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl,
oxo, lower alkylthio, carbamoylmethyl, carbamoylamino,
hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino,
chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl,
halo lower alkoxy substituted benzyl, or lower alkenyl substituted phenyl;
and
R.sup.4 is hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower
(cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkyloxy,
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen or lower alkyl substituted with a
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen, with each of lower (cyclo)alkyl, lower
alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkyloxy or
heterocyclyl ring which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen being unsubstituted or substituted by
carboxy, amino, nitro, cyano, lower alkyl, benzyl, lower alkoxy, hydroxy,
halogen, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl; R.sup.6 is
hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl, lower
alkenyl or a carboxylic acid protecting group selected from benzhydryl,
p-nitrobenzyl, and p-methoxybenzyl; and pharmaceutically compatible,
readily hydrolyzable esters thereof selected from lower alkanoyloxyalkyl
esters, lower alkoxycarbonyloxyalkyl esters,
1-cyclohexyloxycarbonyloxyethyl ester,
(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl ester, phthalidyl esters,
thiophthalidyl esters, lower alkoxymethyl esters, lower
alkanoylaminomethyl esters, benzyl esters, cyanomethyl esters,
(2,2-dimethyl-1-oxopropoxyl)methyl ester,
[2-[(2-mehtylpropoxy)carbonyl]-2-pentenyl]2-(2-methylpropoxy)carbonyl]-2-p
entenyl ester, 1-(1-methylethoxy)carbonyl]oxy]ethyl ester and
3-3-dimethyl-2-oxobutyl ester, and salts of these compounds.
2. The compound of claim 1, wherein R is hydrogen, formyl, unsubstituted
lower alkanoyl, lower alkanoyl substituted by halogen, unsubstituted
carbamoyl, or carbamoyl substituted by hydroxyphenyl or carbamoylphenyl.
3. The compound of claim 2, wherein R is hydrogen, formyl, unsubstituted
lower alkanoyl, lower alkanoyl substituted by halogen, or carbamoyl
substituted by hydroxyphenyl or carbamoylphenyl.
4. The compound of claim 3, wherein R is hydrogen.
5. The compound of claim 4, wherein A is formula (b1).
6. The compound of claim 5, wherein R.sup.3 is unsubstituted aryl or aryl
substituted by hydroxy.
7. The compound of claim 6, wherein R.sup.3 is unsubstituted aryl.
8. The compound of claim 7,
(E)-(1aS,3aR,6bR)-1-oxo-5-styryl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cy
clobut[cd]indene-6-carboxylic acid.
9. The compound of claim 6, wherein R.sup.3 is aryl substituted by hydroxy.
10. The compound of claim 9,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,4,6b-hexa
hydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
11. The compound of claim 5, wherein R.sup.3 is unsubstituted heterocyclyl
or heterocyclyl having a phenyl ring fused thereto.
12. The compound of claim 11, wherein R.sup.3 is unsubstituted
heterocyclyl.
13. The compound of claim 12, wherein the unsubstituted heterocyclyl is
selected from pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
14. The compound of claim 13,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
15. The compound of claim 13,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
16. The compound of claim 13,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
17. The compound of claim 11, wherein R.sup.3 is heterocyclyl having a
phenyl ring fused thereto.
18. The compound of claim 17, wherein heterocyclyl having a phenyl ring
fused thereto is selected from quinolin-2-yl, quinolin-3-yl, and
quinolin-4-yl.
19. The compound of claim 18,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
20. The compound of claim 18,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
21. The compound of claim 3, wherein R is formyl.
22. The compound of claim 21, wherein A is formula (b1).
23. The compound of claim 22, wherein R.sup.3 is unsubstituted heterocyclyl
or heterocyclyl having a phenyl ring is fused thereto.
24. The compound of claim 23, wherein R.sup.3 is unsubstituted
heterocyclyl.
25. The compound of claim 24, wherein unsubstituted heterocyclyl is
selected from pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
26. The compound of claim 25,
(E)-(1aS,3aR,6bR)-2-formyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
27. The compound of claim 3, wherein R is unsubstituted lower alkanoyl.
28. The compound of claim 27, wherein A is formula (b1).
29. The compound of claim 28, wherein R.sup.3 is unsubstituted aryl or aryl
substituted by hydroxy.
30. The compound of claim 29, wherein R.sup.3 is unsubstituted aryl.
31. The compound of claim 30,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-styryl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a
-diaza-cyclobut[cd]indene-6-carboxylic acid.
32. The compound of claim 29, wherein R.sup.3 is aryl substituted by
hydroxy.
33. The compound of claim 32,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
34. The compound of claim 28, wherein R.sup.3 is unsubstituted
heterocyclyl; heterocyclyl substituted by hydroxyphenylcarbamoyl,
carbamoylmethyl, unsubstituted benzyl, halo lower alkoxy substituted
benzyl, or phenyl substituted lower alkenyl; or heterocyclyl having a
phenyl ring fused thereto, the heterocyclyl thereof being unsubstituted or
substituted by carbamoylmethyl.
35. The compound of claim 34, wherein R.sup.3 is unsubstituted
heterocyclyl.
36. The compound of claim 35, wherein the unsubstituted heterocyclyl is
selected from pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
37. The compound of claim 36,
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
38. The compound of claim 36,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
39. The compound of claim 36,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
40. The compound of claim 34, wherein R.sup.3 is heterocyclyl having a
phenyl ring fused thereto.
41. The compound of claim 40, wherein heterocyclyl having a phenyl ring
fused thereto is selected from quinolin-2-yl, quinolin-3-yl, and
quinolin-4-yl.
42. The compound of claim 41,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
43. The compound of claim 41,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
44. The compound of claim 34, wherein R.sup.3 is a heterocyclyl substituted
by hydroxyphenylcarbamoyl, carbamoylmethyl, unsubstituted benzyl, halo
lower alkoxy substituted benzyl, or phenyl substituted lower alkenyl.
45. The compound of claim 3, wherein R is carbamoyl substituted by
carbamoylphenyl.
46. The compound of claim 45, wherein A is formula (b2).
47. The compound of claim 44, wherein the heterocyclyl is substituted by
carbamoylmethyl or unsubstituted benzyl.
48. The compound of claim 46, wherein R.sup.4 is selected from
unsubstituted lower alkyl, lower alkyl substituted by halogen, lower
cycloalkyl, unsubstituted aryl, aryl substituted by hydroxy or nitro,
unsubstituted aralkyl or aralkyl substituted by nitro, heterocyclylalkyl,
unsubstituted heterocyclyl, heterocyclyl substituted by benzyl, R.sup.6
OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5 is hydrogen or
lower alkyl and R.sup.6 is hydrogen or lower alkyl.
49. The compound of claim 48, wherein R.sup.4 is selected from
unsubstituted lower alkyl or lower alkyl substituted by halogen.
50. The compound of claim 49, wherein R.sup.4 is lower alkyl substituted by
halogen.
51. The compound of claim 44, wherein the heterocyclyl is substituted by
unsubstituted benzyl, carbamoylmethyl, hydroxyphenylcarbamoyl, halo lower
alkoxy substituted benzyl, or phenyl substituted lower alkenyl.
52. The compound of claim 50,
(E)-(1aS,3aR,6bR)-2-(4-carbamoyl-phenylcarbamoyl)-1-oxo-5-[2-oxo-1-(2,2,2-
trifluoro-ethyl)-pyrrolidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,
6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
53. A compound of formula II
##STR100##
wherein
A is a group of formula (b1) or (b2)
##STR101##
wherein
R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl,
lower alkoxy, aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5
R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6
COO-- in which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl;
R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl,
lower alkenyl or a carboxylic acid protecting group selected from
benzhydryl, p-nitrobenzyl and p-methoxybenzyl; an unsubstituted
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen; a heterocyclyl which is a 5- or 6-membered
ring optionally containing nitrogen, sulfur and/or oxygen substituted by
lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino,
mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio,
carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower
alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted
benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted
benzyl, lower alkenyl substituted phenyl, --CONR.sup.5 R.sup.6, --CH.sub.2
--CONR.sup.5 R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO--
or R.sup.6 COO-- in which R.sup.5 is hydrogen, lower alkyl or lower
cycloalkyl, R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen,
lower alkyl, lower alkenyl or a carboxylic acid protecting group selected
from benzhydryl, p-nitrobenzyl and p-methoxybenzyl; or a heterocyclyl
which is a 5- or 6-membered ring optionally containing nitrogen, sulfur
and/or oxygen having a phenyl ring fused thereto, the heterocyclyl thereof
being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen,
halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl,
oxo, lower alkylthio, carbamoylmethyl, carbamoylamino,
hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino,
chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl,
halo lower alkoxy substituted benzyl, or lower alkenyl substituted phenyl;
and
R.sup.4 is hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower
(cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkyloxy,
heterocyclyl or heterocyclylalkyl, with each of lower (cyclo)alkyl, lower
alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkyloxy or
heterocyclyl ring being unsubstituted or substituted by carboxy, amino,
nitro, cyano, lower alkyl, benzyl, lower alkoxy, hydroxy, halogen,
--CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 is hydrogen, lower alkyl ol lower cycloalkyl; R.sup.6 is
hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl, lower
alkenyl or a carboxylic acid protecting group selected from benzhydryl,
p-nitrobenzyl and p-methoxybenzyl;
R.sup.S is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl
substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower
alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower
(cyclo)alkanoyl; or lower (cyclo)alkanoyl substituted by halogen, cyano,
carbamoyl-lower alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower
alkylamino, unsubstituted lower (cyclo)alkylsulphonyl; or lower
(cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower
alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino;
unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl,
lower alkoxycarbonyl-lower alkyl, benzyloxy-carbonyl-lower alkyl,
carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure
of the formula
Q--X--CO-- (a1)
or
Q--X--SO.sub.2 -- (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen;
X is a direct bond or a group --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.dbd.CH--, --NH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --CH(NH.sub.2)--,
--CH.sub.2 CH.sub.2 NH--, --C(.dbd.NOCH.sub.3)--, --OCH.sub.2 -- or
--SCH.sub.2 --; or is an amino protecting group; and
R.sup.S1 is a carboxy protecting group selected from benzhydryl, t-butyl,
allyl, p-nitrobenzyl and p-methoxybenzyl.
54. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula I
##STR102##
wherein
R is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl
substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower
alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower
(cyclo)alkanoyl; or lower (cyclo)alkanoyl substituted by halogen, cyano,
carbamoyl-lower alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower
alkylamino, unsubstituted lower (cyclo)alkylsulphonyl; or lower
(cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower
alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino;
unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl,
lower alkoxycarbonyl-lower alkyl, benzyloxy-carbonyl-lower alkyl,
carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure
of the formula
Q--X--CO-- (a1)
or
Q--X--SO.sub.2 -- (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen;
X is a direct bond or a group --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.dbd.CH--, --NH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --CH(NH.sub.2)--,
--CH.sub.2 CH.sub.2 NH--, --C(.dbd.NOCH.sub.3)--, --OCH.sub.2 -- or
--SCH.sub.2 --; and
A is a group of formula (b1) or (b2)
##STR103##
wherein
R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl,
lower alkoxy, aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5
R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6
COO-- in which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl;
R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl,
lower alkenyl or a carboxylic acid protecting group selected from
benzhydryl, p-nitrobenzyl, and p-methoxybenzyl; an unsubstituted
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen; a heterocyclyl which is a 5- or 6-membered
ring optionally containing nitrogen, sulfur and/or oxygen substituted by
lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino,
mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio,
carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower
alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted
benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted
benzyl, lower alkenyl substituted phenyl, --CONR.sup.5 R.sup.6, --CH.sub.2
--CONR.sup.5 R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO--
or R.sup.6 COO-- in which R.sup.5 is hydrogen, lower alkyl or lower
cycloalkyl; R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen,
lower alkyl, lower alkenyl or a carboxylic acid protecting group selected
from benzhydryl, p-nitrobenzyl, and p-methoxybenzyl; or a heterocyclyl
which is a 5- or 6-membered ring optionally containing nitrogen, sulfur
and/or oxygen having a phenyl ring fused thereto, the heterocyclyl thereof
being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen,
halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl,
oxo, lower alkylthio, carbamoylmethyl, carbamoylamino,
hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino,
chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl,
halo lower alkoxy substituted benzyl, or lower alkenyl substituted phenyl;
and
R.sup.4 is hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower
(cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkyloxy,
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen or lower alkyl substituted with a
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen, with each of lower (cyclo)alkyl, lower
alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkyloxy or
heterocyclyl ring which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen being unsubstituted or substituted by
carboxy, amino, nitro, cyano, lower alkyl, benzyl, lower alkoxy, hydroxy,
halogen, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl; R.sup.6 is
hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl, lower
alkenyl or a carboxylic acid protecting group selected from benzhydryl,
p-nitrobenzyl, and p-methoxybenzyl; and pharmaceutically compatible,
readily hydrolyzable esters thereof selected from lower alkanoyloxyalkyl
esters, lower alkoxycarbonyloxyalkyl esters,
1-cyclohexyloxycarbonyloxyethyl ester,
(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl ester, phthalidyl esters,
thiophthalidyl esters, lower alkoxymethyl esters, lower
alkanoylaminomethyl esters, benzyl esters, cyanomethyl esters,
(2,2-dimethyl-1-oxopropoxyl)methyl ester,
[2-[(2-mehtylpropoxy)carbonyl]-2-pentenyl]
2-(2-methylpropoxy)carbonyl-2-pentenyl ester,
1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester and 3-3-dimethyl-2-oxobutyl
ester, and salts of these compounds
and a pharmaceutically acceptable carrier.
55. A method of treating bacterial infections in a mammal in need of such
treatment which comprises administering a therapeutically effective amount
of a compound of formula I
##STR104##
wherein
R is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl
substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower
alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower
(cyclo)alkanoyl; or lower (cyclo)alkanoyl substituted by halogen, cyano,
carbamoyl-lower alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower
alkylamino, unsubstituted lower (cyclo)alkylsulphonyl; or lower
(cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower
alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino;
unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl,
lower alkoxycarbonyl-lower alkyl, benzyloxy-carbonyl-lower alkyl,
carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure
of the formula
Q--X--CO-- (a1)
or
Q--X--SO.sub.2 -- (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen;
X is a direct bond or a group --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.dbd.CH--, --NH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --CH(NH.sub.2)--,
--CH.sub.2 CH.sub.2 NH--, --C(.dbd.NOCH3)--, --OCH.sub.2 -- or --SCH.sub.2
--; and
A is a group of formula (b1) or (b2)
##STR105##
wherein
R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl,
lower alkoxy, aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5
R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6
COO-- in which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl;
R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl,
lower alkenyl or a carboxylic acid protecting group selected from
benzhydryl, p-nitrobenzyl, and p-methoxybenzyl; an unsubstituted
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen; a heterocyclyl which is a 5- or 6-membered
ring optionally containing nitrogen, sulfur and/or oxygen substituted by
lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino,
mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio,
carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower
alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted
benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted
benzyl, lower alkenyl substituted phenyl, --CONR.sup.5 R.sup.6, --CH.sub.2
--CONR.sup.5 R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO--
or R.sup.6 COO-- in which R.sup.5 is hydrogen, lower alkyl or lower
cycloalkyl; R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen,
lower alkyl, lower alkenyl or a carboxylic acid protecting group selected
from benzhydryl, p-nitrobenzyl, and p-methoxybenzyl; or a heterocyclyl
which is a 5- or 6-membered ring optionally containing nitrogen, sulfur
and/or oxygen having a phenyl ring fused thereto, the heterocyclyl thereof
being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen,
halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl,
oxo, lower alkylthio, carbamoylmethyl, carbamoylamino,
hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino,
chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl,
halo lower alkoxy substituted benzyl, or lower alkenyl substituted phenyl;
and
R.sup.4 is hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower
(cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkyloxy,
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen or lower alkyl substituted with a
heterocyclyl which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen, with each of lower (cyclo)alkyl, lower
alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkyloxy or
heterocyclyl ring which is a 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen being unsubstituted or substituted by
carboxy, amino, nitro, cyano, lower alkyl, benzyl, lower alkoxy, hydroxy,
halogen, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl; R.sup.6 is
hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl, lower
alkenyl or a carboxylic acid protecting group selected from benzhydryl,
p-nitrobenzyl, and p-methoxybenzyl; and pharmaceutically compatible,
readily hydrolyzable esters thereof selected from lower alkanoyloxyalkyl
esters, lower alkoxycarbonyloxyalkyl esters,
1-cyclohexyloxycarbonyloxyethyl ester,
(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl ester, phthalidyl esters,
thiophthalidyl esters, lower alkoxymethyl esters, lower
alkanoylaminomethyl esters, benzyl esters, cyanomethyl esters,
(2,2-dimethyl-1-oxopropoxyl)methyl ester,
[2-[(2-mehtylpropoxy)carbonyl]-2-pentenyl]
2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester,
1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester and 3-3-dimethyl-2-oxobutyl
ester, and salts of these compounds
and a pharmaceutically acceptable carrier.
56. The compound of claim 27, wherein A is formula (b2).
57. The compound of claim 34, wherein the heterocyclyl of the heterocyclyl
having a phenyl ring fused thereto is substituted by carbamoylmethyl.
58. The compound of claim 56, wherein R.sup.4 is selected from
unsubstituted lower alkyl, lower alkyl substituted by halogen, lower
cycloalkyl, unsubstituted aryl, aryl substituted by hydroxy or nitro,
unsubstituted aralkyl or aralkyl substituted by nitro, heterocyclylalkyl,
unsubstituted heterocyclyl, heterocyclyl substituted by benzyl, R.sup.6
OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5 is hydrogen or
lower alkyl and R.sup.6 is hydrogen or lower alkyl.
59. The compound of claim 3, wherein R is lower alkanoyl substituted by
halogen.
60. The compound of claim 59, wherein A is formula (b1).
61. The compound of claim 60, wherein R.sup.3 is unsubstituted
heterocyclyl.
62. The compound of claim 61,
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-2-trifluoroacetyl-1a,2,3,
3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
63. The compound of claim 4, wherein A is formula (b2).
64. The compound of claim 63, wherein R.sup.4 is selected from
unsubstituted lower alkyl, lower alkyl substituted by halogen, lower
cycloalkyl, unsubstituted aryl, aryl substituted by hydroxy or nitro,
unsubstituted aralkyl or aralkyl substituted by nitro, heterocyclylalkyl,
unsubstituted heterocyclyl, heterocyclyl substituted by benzyl, R.sup.6
OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5 is hydrogen or
lower alkyl and R.sup.6 is hydrogen or lower alkyl.
65. The compound of claim 64, wherein R.sup.4 is aryl substituted by
hydroxy.
66. The compound of claim 65,
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3-ylidenem
ethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyl
ic acid.
67. The compound of claim 64, wherein R.sup.4 is aryl substituted by nitro.
68. The compound of claim 67,
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
69. The compound of claim 64, wherein R.sup.4 is unsubstituted aryl.
70. The compound of claim 69,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
71. The compound of claim 64, wherein R.sup.4 is selected from
unsubstituted lower alkyl.
72. The compound of claim 71,
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
73. The compound of claim 64, wherein R.sup.4 is selected from lower alkyl
substituted by halogen.
74. The compound of claim 73,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-yl
idenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-ca
rboxylic acid.
75. The compound of claim 64, wherein R.sup.4 is lower cycloalkyl.
76. The compound of claim 75,
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
77. The compound of claim 64, wherein R.sup.4 is aralkyl substituted by
nitro.
78. The compound of claim 77,
(E)-(1aS,3aR,6bR)-1-oxo-5-2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-ylidenemeth
yl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
79. The compound of claim 64, wherein R.sup.4 is unsubstituted
heterocyclyl.
80. The compound of claim 79,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
81. The compound of claim 64, wherein R.sup.4 is heterocyclyl substituted
by benzyl, R.sup.6 OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5
is hydrogen or lower alkyl and R.sup.6 is hydrogen or lower alkyl, or
heterocyclylalkyl.
82. The compound of claim 81, wherein the heterocyclyl is substituted by
R.sup.6 OCO-- where R.sup.6 is hydrogen or lower alkyl.
83. The compound of claim 82, wherein R.sup.6 is lower alkyl.
84. The compound of claim 83,
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,
6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
85. The compound of claim 64, wherein R.sup.4 is heterocyclylalkyl.
86. The compound of claim 85,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid.
87. The compound of claim 59, wherein A is formula (b2).
88. The compound of claim 87, wherein R.sup.4 is selected from
unsubstituted lower alkyl, lower alkyl substituted by halogen, lower
cycloalkyl, unsubstituted aryl, aryl substituted by hydroxy or nitro,
unsubstituted aralkyl or aralkyl substituted by nitro, heterocyclylalkyl,
unsubstituted heterocyclyl, heterocyclyl substituted by benzyl, R.sup.6
OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5 is hydrogen or
lower alkyl and R.sup.6 is hydrogen or lower alkyl.
89. The compound of claim 58, wherein R.sup.4 is aryl substituted by
hydroxy.
90. The compound of claim 89,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3
-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6
-carboxylic acid.
91. The compound of claim 88, wherein R.sup.4 is aryl substituted by nitro.
92. The compound of claim 91,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-y
lidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid.
93. The compound of claim 88, wherein R.sup.4 is unsubstituted aryl.
94. The compound of claim 93,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid.
95. The compound of claim 88, wherein R.sup.4 is selected from
unsubstituted lower alkyl.
96. The compound of claim 95,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-isobutyl-pyrrolidin-3-ylidenem
ethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyl
ic acid.
97. The compound of claim 88, wherein R.sup.4 is selected from lower alkyl
substituted by halogen.
98. The compound of claim 97,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrroli
din-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-6-carboxylic acid.
99. The compound of claim 88, wherein R.sup.4 is lower cycloalkyl.
100. The compound of claim 99,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylide
nemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid.
101. The compound of claim 88, wherein R.sup.4 is aralkyl substituted by
nitro.
102. The compound of claim 101,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-y
lidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid.
103. The compound of claim 88, wherein R.sup.4 is unsubstituted
heterocyclyl.
104. The compound of claim 103,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid.
105. The compound of claim 88, wherein R.sup.4 is heterocyclyl substituted
by benzyl, R.sup.6 OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5
is hydrogen or lower alkyl and R.sup.6 is hydrogen or lower alkyl, or
heterocyclylalkyl.
106. The compound of claim 105, wherein the heterocyclyl is substituted by
R.sup.6 OCO-- where R.sup.6 is hydrogen or lower alkyl.
107. The compound of claim 106, wherein R.sup.6 is lower alkyl.
108. The compound of claim 107,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-
oxo-pyrrolidin-3-ylidenemethyl]-1a,2,3,3a,4,
6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid.
109. The compound of claim 88, wherein R.sup.4 is heterocyclylalkyl.
110. The compound of claim 109,
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(thiophen-2-yl-methyl)-pyrroli
din-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-6-carboxylic acid.
111. The compound of claim 88, wherein R.sup.4 is heterocyclylalkyl.
112. The compound of claim 111,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-yl-methyl)-pyrrolidin-3-yli
denemethyl]-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-6-carboxylic acid.
113. The compound of claim 88, wherein R.sup.4 is aryl substituted by
nitro.
114. The compound of claim 113,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(3-nitro-phenyl)-pyrrolidin-3-ylideneme
thyl]-2-trifluoro-acetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd
]indene-6-carboxylic acid.
115. The compound of claim 88, wherein R.sup.4 is unsubstituted aryl.
116. The compound of claim 115,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-2-tr
ifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid.
117. The compound of claim 88, wherein R.sup.4 is lower cycloalkyl.
118. The compound of claim 117,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-cyclopropyl-pyrrolidin-3-ylidenemethyl]
-2-trifluoro-acetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inde
ne-6-carboxylic acid.
119. The compound of claim 88, wherein R.sup.4 is unsubstituted
heterocyclyl.
120. The compound of claim 119,
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-2-trifluoro-acetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-6-carboxylic acid.
121. The compound of claim 88, wherein R.sup.4 is heterocyclyl substituted
by benzyl, R.sup.6 OCO-- or --CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5
is hydrogen or lower alkyl and R.sup.6 is hydrogen or lower alkyl.
122. The compound of claim 121, wherein the heterocyclyl is substituted by
--CH.sub.2 --CONR.sup.5 R.sup.6 where R.sup.5 is hydrogen or lower alkyl
and R.sup.6 is hydrogen or lower alkyl.
123. The compound of claim 121, wherein the heterocyclyl is substituted by
benzyl.
124. The compound of claim 122, wherein R.sup.6 is hydrogen and R.sup.5 is
hydrogen.
Description
The present invention is concerned with compounds of formula I
##STR3##
wherein
R is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl
substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower
alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower
(cyclo)alkanoyl or lower (cyclo)alkanoyl substituted by halogen, cyano,
carbamoyl-lower alkoxy, carbamoyl-lower alkylthio, or carbamoyl-lower
alkylamino; unsubstituted lower (cyclo)alkylsulphonyl; or lower
(cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower
alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino;
unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl,
lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl,
carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure
of the formula
Q--X--CO-- (a1)
or
Q--X--SO.sub.2 -- (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen and which is optionally substituted by lower alkyl, lower alkoxy,
lower alkylthio, hydroxy, carbamoyl, carbamoyl methyl, carbamolyamino,
hydroxy phenyl-carbamoyl, sulphamoyl, lower alkanoyloxy, sulphonyloxy,
halogen, amino, methylamino, dimethylamino, chloroacetylamino, and
pyridin-1-yl-acetylamino;
X is a direct bond or a group --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.dbd.CH--, --NH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --CH(NH.sub.2)--,
--CH.sub.2 CH.sub.2 NH--, --C(.dbd.NOCH.sub.3)--, --OCH.sub.2 -- or
--SCH.sub.2 --; and
A is a group of formula (b1) or (b2)
##STR4##
wherein
R.sup.3 is unsubstituted aryl or aryl substituted by one or two
substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl,
lower alkoxy, aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5
R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6
COO-- in which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl;
R.sup.6 is hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl,
lower alkenyl or a carboxylic acid protecting group; an unsubstituted
heterocyclyl; a heterocyclyl substituted by lower alkyl, lower alkoxy,
halogen, halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl,
carboxyl, oxo, lower alkylthio, carbamoylmethyl, carbamoylamino,
hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino,
chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl,
halo lower alkoxy substituted benzyl, lower alkenyl substituted phenyl,
--CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 is hydrogen, lower alkyl or lower cycloalkyl; R.sup.6 is
hydrogen or lower alkyl; and R.sup.7 is hydrogen, lower alkyl, lower
alkenyl or a carboxylic acid protecting group; a heterocyclyl having a
phenyl ring fused thereto, the heterocyclyl thereof being unsubstituted or
substituted by lower alkyl, lower alkoxy, halogen, halo substituted alkyl,
amino, mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio,
carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower
alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted
benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted
benzyl, or lower alkenyl substituted phenyl; and
R.sup.4 is, hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower
(cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoyloxy,
heterocyclyl or heterocyclylalkyl, with each of lower (cyclo)alkyl, lower
alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkoyloxy or
heterocyclyl being unsubstituted or substituted by carboxy, amino, nitro,
cyano, lower alkyl, benzyl, lower alkoxy, hydroxy, halogen, --CONR.sup.5
R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6, --N(R.sup.6)COOR.sup.7, R.sup.6
CO--, R.sup.6 OCO-- or R.sup.6 COO-- in which R.sup.5 is hydrogen, lower
alkyl or lower cycloalkyl; R.sup.6 is hydrogen or lower alkyl; and R.sup.7
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting
group;
and pharmaceutically compatible, readily hydrolyzable esters and salts of
these compounds.
European Patent Application EP-A-0 671 401 describes .beta.-lactams which
have .beta.-lactamase inhibiting and, in part, also antibacterial
properties. The compounds in accordance with the invention differ from
these known compounds by the substituent A.
It has surprisingly been found that compounds in accordance with the
invention have, in addition to their .beta.-lactamase inhibiting
properties, an improved spectrum of activity against gram-positive and
gram-negative microorganisms and also against .beta.-lactamase producing
strains.
These compounds are useful in the control of .beta.-lactamase forming
pathogens in combination with .beta.-lactam antibiotics such as the
penicillins, cephalosporins, penems and carbapenems. They also have an
antibacterial activity themselves and can accordingly also be used alone
against bacterial pathogens.
Objects of the present invention are .beta.-lactams of formula I above and
pharmaceutically compatible salts thereof, the manufacture of these
compounds, medicaments containing a compound of formula I or
pharmaceutically compatible salt thereof as well as the use of compounds
of formula I and of pharmaceutically compatible salts thereof for the
production of medicaments for the control or prevention of infectious
diseases, especially those which are caused by .beta.-lactamase forming
microorganisms.
The terms in brackets set forth in the definition of formula I, e.g. "lower
(cyclo)alkyl", "lower (cyclo)alkanoyl", "lower (cyclo)alkyl-sulphonyl" are
to be understood as being optional, and accordingly "lower alkyl", "lower
alkanoyl" and "lower alkylsulphonyl" as well as "lower cycloalkyl", "lower
cycloalkanoyl" and "lower cycloalkylsulphonyl" are intended.
The term "lower alkyl", taken alone or in combinations, such as "lower
alkoxy", "lower alkylamino", "lower alkylcarbamoyl", "lower alkoxy
carbonyl", "lower alkanoyl" (="lower alkylcarbonyl"), "lower
alkylsulphonyl", "lower alkylthio" and the like, is straight-chain or
branched saturated hydrocarbon residues with 7, preferably 4, carbon
atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl and the like.
"Lower cycloalkyl", taken alone or in corresponding combinations, is cyclic
hydrocarbon residues with 3-6 hydrocarbon atoms, i.e. cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
The term "lower alkenyl", taken alone or in combinations, such as "lower
alkenylmethyl" and "lower alkenylmethoxycarbonyl" embraces unsaturated
hydrocarbon residues with up to 7, preferably up to 4, carbon atoms,
containing a double bond, such as vinyl, allyl and the like.
The term "lower alkynyl" embraces unsaturated hydrocarbon residues with up
to 7, preferably up to 4, carbon atoms containing a triple bond, such as
ethynyl, propargyl and the like.
"Halogen" is fluorine, chlorine, bromine or iodine, especially fluorine.
The "5- or 6-membered ring optionally containing nitrogen, sulphur and/or
oxygen" set forth under R (residue Q) are e.g. phenyl, saturated
heterocycles such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, tetrahydrothienyl and tetrahydrofuryl, and aromatic
heterocycles such as 2-furyl, 3-furyl, thiazolyl, thiadiazolyl,
oxadiazolyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyridinio,
2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, isoxazolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl and pyrimidinyl.
The 5- or 6-membered ring optionally containing nitrogen sulfur and/or
oxygen can also be substituted, e.g. by lower alkyl, lower alkoxy, lower
alkylthio, hydroxy, carbamoyl, carbamoylmethyl, carbamoylamino, hydroxy
phenyl carbamoyl, sulphamoyl, lower alkanoyloxy, sulphonyloxy, halogen,
amino, methylamino, dimethylamino, chloroacetylamino and
pyridin-1-yl-acetylamino as well as those additional substituents found on
the heterocyclic ring as discussed below. Additional substituents include
unsubstituted aryl or aryl substituted by one or two substituents selected
from halogen, hydroxy, cyano, nitro, lower alkyl, lower alkoxy, aralkyl,
--CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R5 signifies hydrogen, lower alkyl or lower cycloalkyl; R.sup.6
signifies hydrogen or lower alkyl; and R.sup.7 signifies hydrogen, lower
alkyl, lower alkenyl or a carboxylic acid protecting group. N-Heterocycles
can also be substituted by oxo. Examples of such substituted rings are
4-tolyl, 4-sulphamoyl-phenyl, 4-hydroxyphenyl, 4-carbamoylphenyl,
3,4-dihydroxyphenyl, 3-methyl-(2-furyl), 1-methyl-1H-tetrazol-5-yl,
4-anisyl, 3,4,5-trimethoxyphenyl, 4-chlorophenyl, 4-fluoro-(2-pyridyl),
2-amino-4-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, p-amino-phenyl,
p-(chloroacetylamino)-phenyl, 3,4-disulphonyloxy-phenyl,
3,4-diacetoxyphenyl, 2-oxo-pyrrolidinyl-3-yl, 2-oxo-tetrahydrothien-3-yl,
3-methoxy-isoxazol-5-yl, 1,1-dioxo-tetrahydrothien-3-yl,
3-hydroxy-isoxazol-5-yl, 5-amino-1,3,4-thiadiazol-2-yl,
5-(pyridin-1-yl-acetylamino)-1,3,4-thiadiazol-2-yl and
1-methyl-pyridin-4-yl. The 5- or 6-membered ring optionally containing
nitrogen, sulfur and/or oxygen can also be optionally fused to another
ring, for example, especially a phenyl ring, such as e.g. indolyl,
1H-benzotriazol-2-yl, 2-oxo-2H-1-benzopyran-7-yl or
2-oxo-4-(trifluoromethyl)-2H-1-benzopyran-7-yl, a saturated 5- or
6-membered carbocyclic ring, such as e.g. in 2,3-cyclopenteno-4-pyridyl
and 2,3-cyclohexeno-4-pyridyl, or a 5- or 6-membered heterocycle, such as
e.g. benzimidazol-5-yl, 1H-benzotriazol-4-yl or
2-carbamoyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl.
The term "aryl" set forth under R.sup.3 and R.sup.4 embraces phenyl or
polynuclear aromatic such as naphthyl, anthryl or phenanthryl residues
which are unsubstituted or are mono- or disubstituted by halogen, hydroxy,
cyano, nitro, lower alkyl or lower alkoxy.
The term "aralkyl" set forth under R.sup.4 embraces a lower alkyl group
which is substituted by an aryl group, as defined above, such as e.g.
benzyl.
The term "aryloxy" set forth under R.sup.4 embraces aryl-O--.
The term "aralkyloxy" as used herein refers to an oxygen radical having an
aralkyl substituent.
The term "heterocyclyl" set forth under R.sup.3 and R.sup.4 embraces a 5-
or 6-membered ring optionally containing nitrogen, sulphur and/or oxygen,
moieties such as e.g. pyridyl, pyridiniumyl, pyrazinyl, piperidyl,
piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl,
pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, triazinyl, imidazolyl,
thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1H-tetrazolyl, 2H-tetrazolyl, thienyl, furyl, hexamethylene-iminyl,
1H-azepinyl, thiophenyl, tetrahydrothiophenyl, 1,2,5-oxadithiolyl,
isoxazolyl, isothiazolyl, 4H-1,2,4-oxadiazinyl, 1,2,5-oxathiazinyl,
1,2,3,5-oxathiadiazinyl, 1,3,4-thiadiazepinyl, 1,2,5,6-oxatriazepinyl,
1,6,3,4-dioxadithiophenyl, oxazolidinyl, tetrahydrothienyl, quinolinyl,
quinoliniumyl and the like. Substituents on the heterocyclic ring
comprise: lower alkyl groups such as methyl, ethyl, propyl, etc., lower
alkoxy groups such as methoxy, ethoxy etc., halogens such as fluorine,
chlorine, bromine etc., halo-substituted alkyl groups such as
trifluoromethyl, trichloroethyl etc., amino, mercapto, hydroxyl, carbamoyl
or carboxyl groups as well as those additional substituents found on the
5- or 6-membered ring optionally containing nitrogen, sulfur and/or oxygen
as discussed above. A further substituent is the oxo group such as in
2-oxo-oxazolidin-3-yl, 1,1-dioxo-tetrahydrothien-3-yl. Further examples
for substituted heterocycles are 6-methoxy-pyridin-3-yl,
5-methyl-isoxazol-3-yl, 1-methyl-4-pyridinio. Additional substituents
include, unsubstituted aryl or aryl substituted by one or two substituents
selected from halogen, hydroxy, cyano, nitro, lower alkyl, lower alkoxy,
aralkyl, --CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 signifies hydrogen, lower alkyl or lower cycloalkyl; R.sup.6
signifies hydrogen or lower alkyl; and R.sup.7 signifies hydrogen, lower
alkyl, lower alkenyl or a carboxylic acid protecting group, aralkyl, and
--CONR.sup.5 R.sup.6, --CH.sub.2 --CONR.sup.5 R.sup.6,
--N(R.sup.6)COOR.sup.7, R.sup.6 CO--, R.sup.6 OCO-- or R.sup.6 COO-- in
which R.sup.5 signifies hydrogen, lower alkyl or lower cycloalkyl; R.sup.6
signifies hydrogen or lower alkyl; and R.sup.7 signifies hydrogen, lower
alkyl, lower alkenyl or a carboxylic acid protecting group
The term "heterocyclylalkyl" set forth under R.sup.4 embraces a lower alkyl
group which is substituted by a heterocyclyl group, such as e.g.
thiophen-2 yl-methyl.
The term "amino protecting groups" refers to protecting groups
conventionally used to replace an acidic proton of an amino group.
Examples of such groups are described in Green, T., Protective Groups in
Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp.
218-287, herein incorporated by reference. These examples include the
carbamates of methyl, cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl,
diisopropylmethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
2-furanylmethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-iodoethyl,
2-trimethylsilylethyl, 2-methylthioethyl, 2-methylsulfonylethyl,
2-(p-toluenesulfonyl)ethyl, 2-phosphonioethyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-diphenyl-3-(N,N-diethylamino)propyl, 1-methyl-1-(1-adamantyl)ethyl,
1-methyl-1-phenylethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
1-methyl-1-(4-biphenylyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl,
1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1,1-diemthyl-2-cyanoethyl, isobutyl, t-butyl, t-amyl, cyclobutyl,
1-methylcyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl,
1-adamantyl, isobornyl, vinyl, allyl, cinnamyl, phenyl,
2,4,6-tri-t-butylphenyl, m-nitrophenyl, S-phenyl, 8-quinolyl,
N-hydroxypiperidinyl, 4-(1,4-dimethylpiperdinyl),
4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-trimethylbenzyl,
p-methoxybenzyl, 3,5-dimethoxybenzyl, p-decyloxybenzyl, p-nitrobenzyl,
o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, p-bromobenzyl, chlorobenzyl,
2,4-dichlorobenzyl, p-cyanobenzyl, o-(N,N-dimethylcarboxamide)benzyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)-benzyl, p-(phenylazo)benzyl,
p-(p'-methoxyphenylazo)benzyl, 5-benzisoxazolylmethyl, 9-anthrylmethyl,
diphenylmethyl, phenyl(o-nitrophenyl)methyl, di(2-pyridyl)methyl,
1-methyl-1-(4-pyridyl)-ethyl, isonicotinyl, S-benzyl,
N'-piperidinylcarbonyl, N'-p-touluenesulfonyl-aminocarbonyl,
N'-phenylaminothiocarbonyl; the amides of N-formyl, N-acetyl,
N-chloroacetyl, N-dichloroacetyl, N-trichloroacetyl, N-trifluoroacetyl,
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,
N-acetylpyridinium, N-(N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)propionyl,
N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)-propionyl, N-4-chlorobutyryl,
N-isobutyryl, N-o-nitrocinnamoyl, N-picolinoyl, N-(N'acetylmethionyl),
N-(N'benzoyl-phenylalkanyl), N-benzoyl, N-p-phenylbenzoyl,
N-p-methoxybenzoyl, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,
N-p-P-benzoyl; the cyclic imides of N-phthaloyl, N-2,3-diphenylmaleoyl,
N-dithiasuccinoyl; N-allyl, N-allyloxycarbonyl, N-phenacyl,
N-3-acetoxypropyl, N-(4-nitro-1-cyclohexyl-2-oxo-3-pyrrolin-3-yl),
quaternary ammonium salts, N-methoxymethyl, N-2-chloroethoxymethyl,
N-benzyloxymethyl, N-pivaloyloxymethyl,
N-[1-(alkoxycarbonylamino)-2,2,2-trifluoro]ethyl,
N-[1-trifluoromethyl-1-(p-chlorophenoxymethoxy)-2,2,2-trifluoro]ethyl,
N-2-tetrahydro-pyranyl, N-2,4-dinitrophenyl, N-benzyl,
N-3,4-dimethoxybenzyl, N-o-nitrobenzyl, N-di(p-methoxyphenyl)methyl,
N-triphenylmethyl, N-(p-methoxyphenyl)diphenylmethyl,
N-diphenyl-4-pyridylmethyl, M-2-picolyl N'-oxide, N-5-dibenzosuberyl,
N-(N',N'-dimethylaminomethylene), N,N'-isopropylidene, N-benzylidene,
N-p-methoxybenzyidene, N-p-nitrobenzylidene, N-salicylidene,
N-5-chlorosalicylidene, N-diphenylmethylene,
N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, N-(acylvinyl),
N-(5,5-dimethyl-3-oxo-1-cyclohexenyl), N-borane,
N-[phenyl(pentacarbonylchromium or -tungsten)]carbonyl, N-copper or N-zinc
chelate, N-nitro, N-nitroso, N-oxide, N-diphenyl-phosphinyl,
N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-diethyl phosphoryl,
N-dibenzyl phosphoryl, N-diphenyl phosphoryl, N-trimethylsilyl,
N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,
N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,
N-benzenesulfonyl, N-p-methoxybenzenesulfonyl,
N-2,4,6-trimethylbenzensulfonyl, N-toluenesulfonyl, N-benzylsulfonyl,
N-p-methylbenzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl.
Other amino protecting groups include t-butoxycarbonyl (abbreviated BOC),
benzyloxycarbonyl and allyloxycarbonyl.
The term "carboxylic acid protecting group" refers to protecting groups
conventionally used to replace the acidic proton of a carboxylic acid.
Examples of such groups are described in Greene, T., Protective Groups in
Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and Sons, Inc.
1981), incorporated herein by reference. These examples include
methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,
methoxyethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl,
.alpha.-methylphenacyl, p-methoxyphenacyl, diacylmethyl,
N-phthalimidomethyl, ethyl, 2,2,2-trichloroethyl, 2-haloethyl,
.omega.-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, cinnamyl,
phenyl, p-methylthiophenyl, benzyl, triphenylmethyl, diphenylmethyl,
bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl,
5-dibenzosuberyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl,
p-nitrobenzyl, p-methoxybenzyl, piperonyl, 4-picolyl, trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, i-propyl-dimethylsilyl,
phenyldimethylsilyl, S-t-butyl, S-phenyl, S-2-pyridyl,
N-hydroxypiperidinyl, N-hydroxysuccinimidoyl, N-hydroxyphthalimidoyl,
N-hydroxybenzotriazolyl, O-acyl oximes, 2,4-dinitrophenylsulfenyl,
2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,
5-alkyl-4-oxo-1,3-dioxolanes, triethylstannyl, tri-n-butylstannyl; the
amides or hydrazides of N,N-dimethylamino, pyrrolidinyl, piperidinyl,
o-nitrophenyl, 7-nitroindolyl, 8-nitrotetra-hydroquinolyl,
p-benzenesulfonamide, hydrazides, N-phenylhydrazide,
N,N'-diisopropylhydrazide. Preferred are benzyhydryl, t-butyl,
p-nitrobenzyl, p-methoxybenzyl and allyl.
One preferred sub-group of R has formula (a)
##STR5##
wherein R.sup.1 represents hydrogen, hydroxy, carbamoyl or sulphamoyl and
m, n and p each represent 0 or 1.
Sub-groups of (a) are:
##STR6##
Preferred groups R are 4-hydroxyphenylcarbamoyl,
4-carbamoylphenylcarbamoyl, formyl, acetyl, trifluoroacetyl,
methanesulphonyl or a residue of formula (a5)
##STR7##
Preferred residues R.sup.3 in a group of the formula
##STR8##
set forth under A are: phenyl, substituted phenyl such as e.g.
p-hydroxyphenyl, pyridin-2-, -3- or -4-yl, quinolin-2-, -3- or -4-yl, and
pyridin-1-ium-2- or -3-yl residues such as e.g. residues of the following
formulae
##STR9##
as well as 1-carbamoylmethyl-quinolin-1-ium-3-yl residues of the following
formula
##STR10##
Preferred significances for R.sup.4 in a group of the formula
##STR11##
set forth under A are:
2,2,2-trifluoroethyl
isobutyl,
cyclopropyl,
phenyl,
p-hydroxyphenyl,
m-nitrophenyl,
p-nitrobenzyl,
pyridin-2-, -3- or -4-yl,
pyridin-1-ium-2-, -3- or -4- yl such as e.g. 1-benzyl-pyridin-1-ium-2-yl,
1-benzyl-pyridin-1-ium-3-yl, 1-benzyl-pyridin-1-ium-4-yl,
4-trifluoromethoxy-benzyl-pyridin-1-ium-3-yl,
1-carbamoylmethyl-pyridin-1-ium-2-yl,
1-carbamoylmethyl-pyridin-1-ium-3-yl, 1-carbamoylmethyl-pyridin-1-ium-4-yl
and 4-hydroxyphenylcarbamoyl-methyl-pyridin-1-ium-3-yl,
quinolyl-3-yl, quinolyl-2-yl, 1-carbamoylmethyl-quinolin-1-ium-3-yl,
thiophen-2-yl-methyl
ethoxycarbonyl-piperidin-4-yl,
pyrazinyl,
pyridazinyl,
pyrimidin-2-yl,
thiadiazolyl,
2-oxotetrahydrofuranyl,
tetrazol-5-yl-methyl,
tetrahydrofuranyl and
benzimidazolyl.
Especially preferred compounds of formula I and, respectively, their salts
are:
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3-
ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-
carboxylic acid sodium salt (1:1) (Example 24)
##STR12##
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrroli
din-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-6-carboxylic acid sodium salt (1:1) (Example 25)
##STR13##
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidi
n-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1h-2,6a-diaza-cyclobut[cd]inden
e-6-carboxylic acid sodium salt (1:1) (Example 27)
##STR14##
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-isobutyl-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyli
c acid sodium salt (1:1) (Example 28)
##STR15##
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-yliden
emethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbox
ylic acid sodium salt (1:1) (Example 29)
##STR16##
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylide
nemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid sodium salt (1:1) (Example 33)
##STR17##
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-benzyl-pyridin-1-ium-3-yl)-vinyl]-1-oxo-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
sodium salt (1:1) (Example 66)
##STR18##
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-carbamoylmethyl-pyridin-1-ium-3-yl)-viny
l]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbox
ylic acid sodium salt (1:1) (Example 67)
##STR19##
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-[1-[(4-hydroxyphenyl-carbamoyl)-methyl]-pyr
idin-1-ium-3-yl)-vinyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-6-carboxylic acid sodium salt (1:1) (Example 70)
##STR20##
(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[(E)-2-[1-[(E)-3-phenyl-allyl]-pyridin-1-ium
-3-yl)-vinyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid sodium salt (1:1) (Example 69)
##STR21##
As readily hydrolyzable esters of the compounds of formula I there are to
be understood compounds of formula I in which the carboxy group or carboxy
groups (e.g. the 6-carboxy group) is/are present in the form of a readily
hydrolyzable ester group. Examples of such esters, which can be of the
conventional type, are the lower alkanoyloxyalkyl esters, e.g. the
acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and the
1-pivaloyloxyethyl esters; the lower alkoxycarbonyloxyalkyl esters, e.g.
the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and the
1-isopropoxycarbonyloxyethyl esters; the 1-cyclohexyloxycarbonyloxyethyl
ester; the (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl ester; the lactonyl
esters, e.g. the phthalidyl and the thiophthalidyl esters; the lower
alkoxymethyl esters, e.g. the methoxymethyl ester, and the lower
alkanoylaminomethyl esters, e.g. the acetamidomethyl ester. Other esters,
e.g. the benzyl and cyanomethyl esters, can also be used. Further readily
hydrolyzable esters are the (2,2-dimethyl-1-oxopropoxy)methyl ester, the
2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester, the
1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester and the
3,3-dimethyl-2-oxobutyl ester.
Examples of salts of the compounds of formula I are alkali metal salts,
such as the sodium salt and the potassium salt; ammonium salts; alkaline
earth metal salts, such as the calcium salt; salts with organic bases,
such as salts with amines, e.g. salts with N-ethylpiperidine, procaine,
dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines,
as well as salts with amino acids, such as e.g. salts with arginine or
lysine.
The compounds of formula I in accordance with the invention as well as
their pharmaceutically compatible salts can be made in accordance with the
invention by
a) cleaving off the carboxy protecting group and an amino protecting group
which may be present in a compound of formula II
##STR22##
in which A has the significance given above, R.sup.S has the significance
given for R or is an amino protecting group and R.sup.S1 represents a
carboxy protecting group,
and, if desired, treating a compound of formula III
##STR23##
in which A has the significance given above, which may be obtained with an
agent yielding the residue R and, if necessary, cleaving off any
protecting groups still present, or
b) for making a readily hydrolyzable ester of a compound of formula I,
subjecting a carboxylic acid of formula I to a corresponding
esterification, or
c) for making pharmaceutically compatible salts of a compound of formula I,
converting a compound of formula I into such a salt.
The cleavage of protecting groups in compounds of formula II with R.sup.S1
=t-butyl or R.sup.S =t-butoxycarbonyl is effected by treatment with an
acidic agent, preferably with trifluoroacetic acid, in an organic solvent
such as methylene chloride, optionally in the presence of anisole, phenol,
cresol or triethylsilane, or also with hydrogen chloride in an organic
solvent such as dioxan, tetrahydrofuran or methylene chloride. The
temperature preferably lies between -20.degree. C. and room temperature.
Analogous intermediates with other protecting groups (e.g.
benzyloxycarbonyl or chloroacetyl in position 2; p-nitrobenzyl, benzyl or
benzylhydryl in position 6) are also suitable for the above protecting
group cleavage. The starting materials are prepared analogously and the
protecting group cleavage is carried out in a manner known per se, e.g.:
Position 2
Benzyloxycarbonyl: hydrogenation with palladium/carbon or treatment with
palladium/carbon and 1,4-cyclohexadiene in an organic solvent such as
ethanol, tetrahydrofuran, dioxan, ethyl acetate or dimethylformamide
(optionally aqueous) at about 0-80.degree. C.;
chloroacetyl: using thiourea in a polar solvent, preferably in water at
neutral pH, and about 0-30.degree. C.; or also with an alkali metal
bicarbonate, e.g. sodium bicarbonate, in methanol and/or tetrahydrofuran
(optionally aqueous) at about 0-30.degree. C.
Position 6
Benzyl and p-nitrobenzyl: hydrogenation with palladium/carbon or palladium
oxide at about 0.degree. C. to 80.degree. C. in an organic solvent such as
ethyl acetate, methanol or tetrahydrofuran, or in water, optionally in the
presence of an acid such as acetic acid or hydrochloric acid; or
hydrolysis in the presence of sodium sulphide at about 0.degree. C. to
room temperature in a solvent such as e.g. dimethylformamide (preferably
aqueous).
Benzhydryl: using m-cresol at about 50.degree. C.
In order to introduce a residue R in position 2, the compound of formula
III is e.g. acylated with an acid of the formula ROH or with one of its
reactive derivatives.
For making the readily hydrolyzable esters of the carboxylic acids of
formula I in accordance with variant b) of the process in accordance with
the invention, the carboxylic acid is preferably reacted with the
corresponding halide, preferably with the iodide, which contains the ester
group. The reaction can be accelerated with the aid of a base, e.g. an
alkali metal hydroxide or carbonate or an organic amine such as
triethylamine. The esterification is preferably carried out in an inert
organic solvent such as dimethylacetamide, hexamethylphosphoric acid
triamide, dimethyl sulphoxide or, preferably, dimethylformamide. The
temperature preferably lies in the range of about 0-40.degree. C.
The making of the salts of the compounds of formula I in accordance with
variant c) of the process in accordance with the invention can be effected
in a manner known per se, e.g. by reacting the carboxylic acid of formula
I with an equimolar amount of the desired base, conveniently in a solvent
such as water or in an organic solvent such as ethanol, methanol, acetone
and the like. Correspondingly, salt formation is brought about by addition
of an organic or inorganic acid. The temperature at which the salt
formation is carried out is not critical, it generally lies at room
temperature, but can also lie slightly thereover or thereunder, for
example in the range of 0.degree. C. to +50.degree. C.
The following Reaction Schemes I and II illustrate the process for making
the products in accordance with the invention and, respectively, of the
intermediates which occur in the process. Scheme I shows the making of
compounds in which residue A is a N-substituted
2-oxo-pyrrolidin-3-ylidene-methyl group. Scheme II shows the making of
compounds in which residue A is a substituted ethene-1,2-diyl group.
##STR24##
##STR25##
The symbols have the following significances in Reaction Schemes I and II:
R.sup.S2 =a carboxy protecting group, preferably t-butyl;
R.sup.S =an amino protecting group, preferably t-butoxy-carbonyl;
R.sup.3 =significance given under formula (b1);
R.sup.4 =significance given under formula (b2);
R.sup.5 =benzyl, methylcarbamoyl;
R.sup.6 =benzyl, 4-trifluoromethoxy-benzyl, methylcarbamoyl,
4-hydroxy-phenylcarbamoyl-methyl;
R.sup.11 =hydrogen, lower alkyl, halo-substituted lower alkyl such as e.g.
trifluoromethyl, 4-carbamoyl-phenylamino;
X=halogen.
Scheme 1
(1).fwdarw.(2)
The oxidation of the 5-hydroxy compound (1) to the corresponding aldehyde
(2) takes place in the presence of the
2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO).
The TEMPO-catalyzed oxidation is effected in the presence of a suitable
solvent such as methylene chloride and the like.
The oxidation system contains a base, e.g. sodium acetate, sodium
bicarbonate and the like, for the neutralization of the resulting
hydrochloric acid.
The oxidation can be conveniently effected in a temperature range of
-15.degree. C.-50.degree. C., preferably at 0.degree. C.-5.degree. C.
Conveniently, the oxidation is carried out under atmospheric pressure.
(2).fwdarw.(3)
The aldehyde (2) is reacted with a Wittig reagent to give the addition
product (3). The reaction is carried out in the presence of a base,
preferably in the presence of sodium hydride or lithium hydride. Tertiary
amines or organolithium compounds are also suitable. Water-miscible
solvents such as acetone, tetrahydrofuran, methylene chloride, chloroform,
dichloroethane and alcohols are suitable solvents. The reaction is
effected in a temperature range of (-20).degree. C. to 25.degree. C.
The reaction of the aldehyde (2) with the Wittig reagent can also be
effected by heating under reflux in epoxybutane.
(3).fwdarw.(4)
The protecting groups are removed by reaction with e.g. trifluoroacetic
acid in a temperature range of (-20).degree. C. to room temperature.
(4).fwdarw.(5) The acylation of compound (4) is effected with acylating
agents such as corresponding acids of the formula ROH in the presence of
2-halopyridinium salts, e.g. of 2-chloro- or 2-fluoro-1-methylpyridinium
chloride or tosylate, or also in the presence of carbonyldiimidazole or
N,N'-dicyclohexylcarbodiimide, the latter preferably together with
N-hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxyphthalimide.
Corresponding reactive derivatives of the carboxylic acid, such as e.g.
the acid halide (preferably the chloride), acid anhydride or acid azide,
can also be used. The corresponding thiol esters, such as e.g.
2-benzthiazolyl thioester, as well as hydroxybenztriazole ester,
N-hydroxysuccinimide ester or N-hydroxyphthalimide ester are likewise
useable. The reaction is preferably carried out in an organic solvent or
solvent mixture, e.g. acetone, methylene chloride, tetrahydrofuran,
dioxan, dimethylacetamide, dimethylformamide, dimethyl sulphoxide or
acetonitrile. The temperature generally lies between (-30).degree. C. and
room temperature.
(5).fwdarw.(6)
When the residue R.sup.4 includes a nitrogen-containing group such as
pyridyl, piperidino or quinolinyl, then a quaternisation of the nitrogen
atom can be effected by reaction with benzyl bromide or bromoacetamide.
Scheme 2
(1).fwdarw.(7).fwdarw.(8)
The reaction of the 5-hydroxy compound (1) with methanesulphonyl
chloride/Cal.sub.2 and triphenylphosphine gives the Wittig reagent (7)
which can then be converted into the addition product (8) by reaction with
an aromatic aldehyde.
(8).fwdarw.(9).fwdarw.(10)
The removal of the protecting groups, the acylation and, if desired, the
quaternisation are effected under comparable conditions to those set forth
under Scheme 1,
(3).fwdarw.(4).fwdarw.(5).fwdarw.(6)
As mentioned earlier, the compounds of formula I in accordance with the
invention and pharmaceutically compatible salts exhibit, in addition to
their .beta.-lactamase-inhibiting activity, an improved spectrum of
activity against gram-positive and gram-negative microorganisms as well as
against .beta.-lactamase producing strains.
These therapeutically valuable properties can be determined in vitro as
illustrated hereinafter.
A. Isolation of the .beta.-lactamases
Various .beta.-lactamases can be isolated from penicillin-resistant or
cephalosporin-resistant bacterial strains such as Klebsiella pneumoniae
NCTC 418, Proteus vulgaris 1028, Bacillus licheniformis 749/C, Escherichia
coli SNO1 and Citrobacter freundii 1203. For this purpose, the
corresponding strains are cultivated in Tryptic Soy Broth (Difco) and
harvested by centrifugation in the last logarithmic growth phase (when
necessary 50-100 mg/l of ampicillin are added to the medium towards the
end of the log-phase in order to induce the .beta.-lactamase). The
thus-obtained bacterial mass is treated with 20 mM Tris-HCI buffer (pH
7.0); the cells are broken open with a French press while cooling. The
mixture is centrifuged (20,000 r/min.) for 20-30 minutes and a clear crude
extract is obtained. The purification of the proteins is effected
according to the methods of Cartwright, S. J. & Waley, S. G. [Biochem. J.
221, 505-512 (1980)] and, for B. licheniformis, Ellerby, L. M. et al.
[Biochemistry 29, 5797-5806 (1990)].
B. Determination of the .beta.-lactamase Activity
The determination of the activity of the isolated .beta.-lactamases can be
carried out according to the method of O'Callaghan, C. H. et al.
[Antimicr. Ag. Chemother. 1, 283-288 (1972)] using the chromogenic
cephalosporin nitrocefin (87/312 from Glaxo). The requisite test batch
contains per ml of water: 50 mM phosphate buffer (pH 7.0), 0.1 mM
nitrocefin and sufficient enzyme (.beta.-lactamase) to achieve a
.DELTA.A/min. of about 0.1. The cleavage of the substrate, which is
accompanied by a change in color, is effected at 37.degree. C. and is
followed quantitatively at 482 nm using a spectral photometer.
C. Determination of the .beta.-lactamase-inhibiting Activity of the
Compounds of Formula I
The above-described cleavage of the chromogenic substrate by
.beta.-lactamases (test B.) can be inhibited by the addition of compounds
of formula I (inhibitors). Since it has been found that the inhibitors
irreversibly inactivate the .beta.-lactamase in a time-dependent reaction,
the reaction (cleavage of the substrate) is in each case started by
addition of the substrate after a pre-incubation period of
.beta.-lactamase with inhibitor of 15 minutes. As a measurement for the
affinity of the particular tested inhibitor to the .beta.-lactamase, which
is a measurement of the strength of the inhibitor, there serves that
concentration which inhibits by 50% (IC 50 in .mu.M) the cleavage of the
substrate (nitrocefin) effected under the above test conditions (test B)
in the absence of an inhibitor. 4 to 6 tests with different concentrations
of inhibitor were carried out in order to determine the IC 50. The
determination of the IC 50 was effected by means of a graph.
The results obtained in the above test (test C) are presented in Table 1
hereinafter.
TABLE 1
(Test organism: Citrobacter freundii 1982)
The IC 50 value in .mu.M is given for the products of the following
Examples. This is a measurement for the .beta.-lactamase inhibition.
IC 50
Example No. .mu.M
14 4.6
15 0.019
16 5.0
23 0.016
24 0.264
25 9.81
26 2.1
27 0.716
28 6.5
29 3.3
30 0.362
31 1.00
32 1.94
33 0.276
34 0.211
35 0.011
36 0.105
37 0.077
38 0.036
39 5.58
40 7.2
49 4.5
50 8.6
51 5.0
52 0.553
53 3.3
54 5.1
55 5.3
56 0.247
57 0.020
58 0.033
59 0.022
60 0.027
61 0.024
62 0.010
63 0.067
64 0.011
66 0.550
67 0.141
68 2.62
69 0.310
70 0.081
71 0.865
72 13
D. Antibacterial Activity
The minimum inhibitory concentration in vitro (MIC in .mu.g/ml) of a
compound of formula I against Citrobacter freundii 1982 and Staphylococcus
aureus 887 is measured and compiled in Table 2.
TABLE 2
MIC MIC
C. freundii S. aureus
Example 1982 887
No. .mu.g/ml .mu.g/ml
14 8 16
15 32 8
16 16 8
23 16 16
24 1 1
25 1 4
26 8 2
27 4 2
28 2 8
29 1 16
30 4 1
31 8 2
32 62 8
33 1 2
34 8 4
35 32 4
36 8 4
37 64 4
38 16 4
39 4 2
40 4 2
49 64 8
50 64 64
51 64 4
52 64 4
53 64 2
54 64 64
55 64 4
56 4 1
57 64 4
58 4 2
59 32 1
60 32 2
61 64 64
62 8 2
63 64 0.5
64 32 2
66 8 0.25
67 16 0.25
68 16 0.5
69 32 0.25
70 8 0.25
71 64 0.5
72 64 64
The products in accordance with the invention can be used as medicaments,
e.g. in the form of pharmaceutical preparations, preferably for parenteral
administration.
For this purpose, the products of the present invention are preferably made
into preparations as lyophilisates or dry powders for dilution with
customary agents, such as, for example, water or isotonic common salt
solution.
The products in accordance with the invention can be used as medicaments,
for example, in the form of pharmaceutical preparations for enteral (oral)
administration. The products in accordance with the invention can be
administered, for example, perorally, such as in the form of tablets,
coated tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions or suspensions, or rectally, such as in the form of
suppositories.
Pharmaceutical compositions containing these compounds can be prepared
using conventional procedures familiar to those skilled in the art, such
as by combining the ingredients into a dosage form together with suitable,
non-toxic, inert, therapeutically compatible solid or liquid carrier
materials and, if desired, the usual pharmaceutical adjuvants.
The compositions of this invention can contain, as optional ingredients,
any of the various adjuvants which are used ordinarily in the production
of pharmaceutical preparations. Thus, for example, in formulating the
present compositions into the desired oral dosage forms, one may use, as
optional ingredients, fillers, such as coprecipitated aluminum
hydroxide-calcium carbonate, dicalcium phosphate or lactose;
disintegrating agents, such as maize starch; and lubricating agents, such
as talc, calcium stearate, and the like. It should be fully understood,
however, that the optional ingredients herein named are given by way of
example only and that the invention is not restricted to the use hereof.
Other such adjuvants, which are well known in the art, can be employed in
carrying out this invention.
Suitable as such carrier materials are not only inorganic, but also organic
carrier materials. Thus, for tablets, coated tablets, dragees and hard
gelatine capsules there can be used, for example, lactose, maize starch or
derivatives thereof, talc, stearic acid or its salts. Suitable carriers
for soft gelatine capsules are, for example, vegetable oils, waxes, fats
and semi-solid and liquid polyols (depending on the nature of the active
substance; no carriers are, however, required in the case of soft gelatine
capsules). Suitable carrier materials for the preparation of solutions and
syrups are, for example, water, polyols, saccharose, invert sugar and
glucose. Suitable carrier materials for suppositiories are, for example,
natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
As pharmaceutical adjuvants there are contemplated the usual preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, flavorants, salts for varying the osmotic pressure, buffers,
coating agents and antioxidants.
As mentioned earlier, the compounds in accordance with the invention can be
used in the control or prevention of infectious diseases, especially in
the control of .beta.-lactamase forming pathogens alone or in combination
with .beta.-lactam antibiotics, i.e. antibiotics which contain a
.beta.-lactam ring, for example penicillins such as benzylpenicillin,
piperacillin, phenoxymethylpenicillin, carbenicillin, apalcillin,
methicillin, propicillin, tricarcillin, ampicillin, amoxicillin or
mecillinam, or cephalosporins such as ceftriaxone, ceftazidime, cefetamet,
cefetamet pivoxil, cefotaxime, cefmenoxime, ceftizoxime, cefuroxime,
cephaloridine, cephalotin, cefazolin, cephalexin, cefoxitin, cephacetrile,
cefamandole, cephapirin, cephradine, cephaloglycine,
(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azido
methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or
(E)-2-(isobutoxycarbonyl)-2-pentenyl
(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azido
methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate or also
penems or carbapenems such as imipenem and meropenem. Thereby, the
compounds of formula I or pharmaceutically compatible salts thereof with
bases can be administered before, simultaneously with or after the
administration or intake of .beta.-lactam antibiotics. When the products
in accordance with the invention are administered simultaneously with a
.beta.-lactam antibiotic, then this can be effected by administration as
an ad-hoc combination or in the form of a pharmaceutical combination which
contains a compound of formula I or a pharmaceutically compatible salt
thereof with a base and a .beta.-lactam antibiotic; such pharmaceutical
combinations are also an object of the present invention.
Depending on the nature of the pharmacologically active compound the
pharmaceutical preparations can contain the compound for the prevention
and treatment of infectious diseases in mammals, human and non-human, a
daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to
about 3000 mg, and more especially about 100 mg to about 200 mg is usual,
with those of ordinary skill in the art appreciating that the dosage will
depend also upon the age, conditions of the mammals, and the kind of
diseases being prevented or treated. The daily dosage can be administered
in a single dose or can be divided over several doses. An average single
dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be
contemplated. The ratio of .beta.-lactamase inhibitor (compound of formula
I or pharmaceutically compatible salt thereof with a base) to
.beta.-lactam antibiotic can also vary within wide limits and will be
fitted to the individual requirements in each particular case. In general,
the ratio is about 1:20-1:1.
The following Examples illustrate the invention in more detail. In the
following Examples DMF is dimethylformamide and THF is tetrahydrofuran.
1. Preparation of the 5-hydroxymethyl Compound
Schemes 1 and 2, Compound 1
EXAMPLE 1
Di-t-butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
cyclobut[cd]indene-2,6-dicarboxylate
##STR26##
This compound can be obtained by the following reaction sequence a)-f):
a) Mixture of benzyl (E)- and
(Z)-(1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-e
thoxy)-propylidene]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate
49 g (119.4 mmol) of benzyl
(1S,5S)-6-(3,4-dimethoxybenzyl)-4,7-dioxo-2,6-diazabicyclo[3.2.
0]heptane-2-carboxylate were placed in abs. methylene chloride (250 ml)
and treated dropwise (40 minutes) with
1-[2-(trimethyl-silanyl)-ethoxy]-3-triphenylphosphoranylidene-propan-2-one
(51.9 g; 119.4 mmol) in abs. methylene chloride (125 ml). After 2.5 hours
at room temperature the reaction mixture was poured into 1N aqueous
hydrochloric acid (650 ml) and extracted with methylene chloride
(2.times.300 ml). The combined organic phases were washed with water
(3.times.500 ml) and saturated aqueous sodium chloride solution (500 ml),
dried over magnesium sulphate and concentrated. The residue was
chromatographed over silica gel (1.7 kg, 0.040-0.063 mm particle size)
with ethyl acetate/n-hexane 7:3. Yield: 51.4 g (76%) as a colorless oil.
IR (film): 2840, 1763, 1711 cm.sup.-1 ; MS (ISP): (M+H).sup.+ 567.5.
b) t-Butyl
(1S,4R,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-et
hoxy)-propyl]-2,6-diazabicyclo-[3.2.0]heptane-2-carboxylate
The mixture of benzyl (E)- and
(Z)-(1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-e
thoxy)-propylidene]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (51.4 g;
90.7 mmol) as prepared above was placed in methanol (2 l), treated with
di-t-butyl dicarbonate (29.7 ml; 136 mmol) and hydrogenated over Pd/C (15
g). After 15 hours the reaction mixture was suction filtered, concentrated
and chromatographed over silica gel (1 kg, 0.040-0.063 mm particle size)
with ethyl acetate/n-hexane 1:1. Yield: 25.7 g (53%) as a colorless foam.
IR (film): 1760, 1699, 1591, 1517, 1160, 887, 765 cm.sup.-1 ; MS (ISP):
(M+H).sup.+ 535.4; Microanalysis: C.sub.27 H.sub.42 N.sub.2 O.sub.7 Si;
Calc. C 60.65 H 7.92 N 5.24; Found. C 60.48 H 8.27 N 4.91.
c) t-Butyl
(1S,4R,5R)-7-oxo-4-[2-oxo-3-(2-trimethylsilanylethoxy)-propyl]-2,6-diazabi
cyclo[3.2.0]heptane-2-carboxylate
25.7 g (48 mmol) of t-butyl
(1S,4R,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-et
hoxy)-propyl]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate were placed in
acetonitrile (500 ml) and water (240 ml). The solution was warmed to
60.degree. C. and treated with potassium persulphate (84 g; 310 mmol) in 4
portions at intervals of 1 hour. Simultaneously, the pH value was held at
5 with a 15% aqueous sodium carbonate solution. After 3 hours at
60.degree. C. the suspension obtained was cooled, the pH was adjusted to
7, the mixture was then diluted with water (200 ml) and extracted with
ethyl acetate (2.times.1000 ml). The combined organic phases were washed
with saturated aqueous sodium chloride solution (500 ml), dried over
magnesium sulphate and concentrated. The residue was chromatographed over
silica gel (1000 g; 0.040.times.0.063 mm particle size) with ethyl
acetate/n-hexane 1:1. Yield: 12.7 g (69%) as a colorless solid. M.p.
89-91.degree. C. (ethyl acetate).
IR (KBr): 3294, 1784, 1729, 1696, 1514, 1250 cm.sup.-1 ; Microanalysis:
C.sub.18 H.sub.32 N.sub.2 O.sub.5 Si; Calc. C 56.22 H 8.39 N 7.28; Found C
55.93 H 8.22 N 7.00.
d) Di-t-butyl
(1aS,3aR,6bR)-5-(2-trimethylsilanyl-ethoxy-methyl)-1-oxo-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diazacyclobut[cd]indene-2,6-dicarboxylate
t-Butyl
(1S,4R,5R)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-ethoxy)-propyl]-2,6-diazab
icyclo[3.2.0]heptane-2-carboxylate (12.7 g; 33 mmol) and
methyl-diisopropylamine (7.0 ml; 39.6 mmol) were pre-cooled in abs.
methylene chloride (90 ml) to -5.degree. C. and added to a suspension of
calcium carbonate (13.1 g; 131 mmol) and t-butyloxalyl chloride (6 ml;
39.6 mmol) in abs. methylene chloride (30 ml) while cooling with an ice
bath. After 2 hours at 0.degree. C. the suspension was diluted with
ethanol-free chloroform (120 ml) and filtered over silica gel (70 g;
0.040-0.063 mm particle size). Subsequently, the column was rinsed with
chloroform (120 ml). The combined organic phases were diluted with abs.
toluene (900 ml), treated with triethyl phosphite (11.5 ml; 66 mmol) at
room temperature and heated under reflux conditions for 15 hours. The
solution obtained was concentrated. The residue was dissolved in ethyl
acetate (1200 ml), washed in succession with water (600 ml) and saturated
aqueous sodium chloride solution (600 ml) and dried over magnesium
sulphate. After concentration the residue was chromatographed over silica
gel (600 g; 0.040-0.063 mm particle size) with n-hexane/acetone 9:1.
Yield: 8.7 g (55%) as a colorless solid.
IR (KBr): 1764, 1706, 1248, 836, 776 cm.sup.-1 ; MS (ISP): (M+H).sup.+
481.6.
e) t-Butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
cyclobut[cd]indene-6-carboxylate.
Di-t-butyl
(1aS,3aR,6bR)-5-(2-trimethylsilanyl-ethoxy-methyl)-1-oxo-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diazacyclobut[cd]indene-2,6-dicarboxylate (8.7 g; 18.1
mmol) was dissolved in methylene chloride (30 ml) and added dropwise while
stirring vigorously to trifluoroacetic acid (80 ml) pre-cooled to
-20.degree. C. (the temperature is held between -18 and -20.degree. C.).
After 3 hours at -20.degree. C. the reaction mixture was concentrated at
the same temperature, treated with abs. ether (670 ml) and suction
filtered. Yield: 5.3 g (74%) as a beige solid.
IR (KBr): 3426, 1773, 1710, 1670, 1180, 1077 cm.sup.-1 ; MS (ISP):
(M+H).sup.+ 281.2.
f) Di-t-butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
cyclobut[cd]indene-2,6-dicarboxylate
t-Butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
cyclobut[cd]indene-6-carboxylate (5.3 g; 13.4 mmol) was placed in
dioxan/water 1:1 (150 ml) and treated with sodium bicarbonate (2.2 g; 26.7
mmol) and di-t-butyl dicarbonate (3.7 ml; 16 mmol) at room temperature.
After 1 hour the reaction mixture was poured into saturated aqueous sodium
chloride solution (150 ml), extracted with ethyl acetate (3.times.150 ml),
dried over magnesium sulphate and concentrated. The residue was
chromatographed over silica gel (150 g, 0.040-0.063 mm particle size) with
ethyl acetate. Yield: 3.2 g (63%) as a colorless solid. M.p. 175.degree.
C.
IR (KBr): 1761, 1705, 1631, 1253, 1161, 1117, 1087 cm.sup.-1 ; MS (ISP):
(M+H).sup.+ 381.4.
The 5-hydroxymethyl "compound" can also be obtained according to the
following improved method (reaction sequence a1)-g1)):
a1) n-Butyl (t-butyl-dimethyl-silanyloxy)-acetate
n-Butyl glycolate (231 g; 1.75 mol) and imidazole (345.1 g; 5.07 mol) were
combined at 0.degree. C. The suspension obtained was treated portionwise
with t-butyldimethylchlorosilane (303 g; 2.01 mol) over 1.5 hours. After
20 hours at room temperature the reaction mixture was diluted with
ether/n-hexane 1:1 (1 l) and suction filtered. The crystals were rinsed
thoroughly with ether/n-hexane 1:1 (200 ml). The filtrate was washed in
succession with water (2.times.700 ml) and saturated aqueous sodium
chloride solution (500 ml), dried over magnesium sulphate and
concentrated. The oil obtained was distilled over a Vigreux column (7.5
cm). Yield: 405 g (94%) as a colorless oil (b.p. 78.degree. C./0.98 mm
Hg).
IR (film): 1760, 1225, 1206, 1148, 838, 780 cm.sup.-1 ; MS (EI):
(M+H).sup.+ 247.
b1) Dimethyl [3-(t-butyl-dimethyl-silanyloxy)-propyl]-phosphonate
Dimethyl methanephosphonate (70 ml; 634.8 mmol) was placed in
tetrahydrofuran (1.6 l) at -75.degree. C. and treated at this temperature
with 1.6M n-butyllithium in tetrahydrofuran (437 ml; 700 mmol). After 1.5
hours at -75.degree. C. n-butyl (t-butyl-dimethyl-silanyloxy)-acetate
(52.1 g; 211.6 mmol) in tetrahydrofuran (110 ml) was added and the batch
was stirred for 2 hours at -30.degree. C. The reaction mixture was
subsequently poured into 1N ice-cold aqueous hydrochloric acid (800 ml)
and extracted rapidly with ethyl acetate (2.times.1 l). The combined
organic phases were washed in succession with water (2.times.1 l) and
saturated aqueous sodium chloride solution (500 ml), dried over magnesium
sulphate and concentrated. The residue was azeotroped with toluene
(2.times.300 ml) and distilled (b.p.: 89-95.degree. C.; 0.42 mm Hg).
Yield: 57.2 g (92%) as a colorless oil.
IR (film): 1734, 1257, 1033, 840, 780 cm.sup.-1 ; MS (EI): (M+H).sup.+ 297.
c1) Benzyl (Z) and
(E)-(1S,5R)-4-[3-(t-butyl-dimethyl-silanyl-oxy)-2-oxo-propylidene]-6-(2,4-
dimethoxy-benzyl)-7-oxo-2,6-diaza-bicyclo[3.2.0] heptane-2-carboxylate
Dimethyl [3-(t-butyl-dimethyl-silanyloxy)-propyl]-phosphonate (39.4 g;
133.2 mmol) was dissolved in THF (177 ml) and cooled to 0.degree. C.
Sodium hydride (4.25 g of a 55 to 60% suspension in oil) was added
portionwise in such a manner that the temperature does not rise above
+5.degree. C. After 40 minutes at 0.degree. C. a solution, pre-cooled to
-20.degree. C., of benzyl
(1S,5S)-6-(2,4-dimethoxybenzyl)-4,7-dioxo-2,6-diazabicyclo[3.2.
0]-heptane-2-carboxylate (European Patent Application No. 508 234
discloses the corresponding 3,4-dimethoxybenzyl compound) in ethylene
chloride (750 ml) was added in one portion. The reaction mixture was
stirred for 1 hour at between -6 and -7.degree. C., poured into 1N
ice-cold aqueous hydrochloric acid (140 ml) and extracted with ethyl
acetate (2.times.1 l). The combined organic phases were washed with
saturated aqueous sodium chloride solution (1 l), dried over magnesium
sulphate and concentrated. Yield: 76 g as a yellow oil, which was used in
the next step without further purification.
IR (KBr): 1763, 1711, 1293, 1133, 1034, 838, 781 cm.sup.-1 ; MS (ISP):
(M+H).sup.+ 581.4.
d1) t-Butyl
(1S,4R,5R)-4-[3-(t-butyl-dimethyl-silanyloxy)-2-oxo-propyl]-6-(2,4-dimetho
xy-benzyl)-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-2-carboxylate
The mixture of (Z)- and
(E)-(1S,5R)-4-[3-(t-butyl-dimethyl-silanyloxy)-2-oxo-propylidene]-6-(2,4-d
imethoxybenzyl)-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-2-carboxylate (76 g;
maximal 73.8 mmol) prepared above was dissolved in methanol (900 ml),
treated with di-t-butyl dicarbonate (24.4 ml; 112 mmol) and hydrogenated
over 10% Pd/C (9 g). After 1.5 hours the reaction mixture was suction
filtered, concentrated and chromatographed over silica gel (400 g;
0.063-0.2 mm particle size) with ethyl acetate/n-hexane 1:4. The solid
residue obtained was triturated with n-hexane (200 ml) and suction
filtered. Yield: 17 g (42%) as a colorless powder.
IR (KBr): 1760, 1740, 1688, 1613, 1365, 1261, 1161, 1035, 840, 780
cm.sup.-1 ; MS (ISP): (M+H).sup.+ 549.5.
e1) t-Butyl
(1S,4R,5R)-4-[3-(t-butyl-dimethyl-silanyloxy)-2-oxo-propyl]-7-oxo-2,6-diaz
a-bicyclo[3.2.0]heptane-2-carboxylate
This compound was prepared in analogy to Example 1c) starting from t-butyl
(1S,4R,5R)-4-[3-(t-butyl-dimethyl-silanyloxy)-2-oxo-propyl]-6-(2,4-dimetho
xy-benzyl)-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-2-carboxylate (17 g; 31.0
mmol). The residue obtained was chromatographed over silica gel (400 g;
0.063-0.2 mm particle size) with ethyl acetate/n-hexane 7:3 and
subsequently crystallized from n-hexane. Yield: 7.17 g (58%) as a
colorless powder.
IR (KBr): 1772, 1740, 1700, 1257, 1164, 1107, 839, 780 cm.sup.-1 ; MS
(ISP): (M+H).sup.+ 399.5; (M+NH.sub.4).sup.+ 416.5.
f1) Di-t-butyl
(1aS,3aR,6bR)-5-(t-butyl-dimethyl-silanyloxy-methyl)-1-oxo-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diazacyclobut[cd]indene-2,6-dicarboxylate
t-Butyl
(1S,4R,5R)-4-[3-(t-butyl-dimethyl-silanyloxy)-2-oxo-propyl]-7-oxo-2,6-diaz
a-bicyclo[3.2.0]heptane-2-carboxylate (7.17 g; 18.0 mmol) and
ethyl-diisopropylamine (3.7 ml; 21.6 mmol) were pre-cooled in abs.
methylene chloride (70 ml) to 0.degree. C. and added to a suspension of
calcium carbonate (7.1 g; 71 mmol) and t-butyl-oxalyl chloride (3.55 g;
21.6 mmol) in abs. methylene chloride (50 ml) while cooling with an ice
bath. After 1.5 hours at 0.degree. C. the reaction mixture was diluted
with methylene chloride (200 ml) and washed in succession with 1N ice-cold
aqueous hydrochloric acid (100 ml), ice-cold water (2.times.100 ml) and
ice-cold saturated aqueous sodium chloride solution (100 ml), dried over
magnesium sulphate and concentrated. The residue was dissolved in abs.
toluene (250 ml), treated at room temperature with triethyl phosphite
(6.26 ml; 36 mmol) in abs. toluene (50 ml) and heated under reflux
conditions for 15 hours. The reaction mixture was taken up in ethyl
acetate (100 ml) and washed in succession with water (20 ml) and saturated
aqueous sodium chloride solution (2.times.20 ml), dried over magnesium
sulphate and concentrated. The solid residue was triturated with n-hexane
(200 ml) and suction filtered. Yield: 5.61 g (63%) as a colorless powder.
IR (KBr): 1783, 1703, 1695, 1624, 1258, 1163, 1098, 838, 778 cm.sup.-1 ; MS
(EI): (M-.sup.t BuO.) 421; Microanalysis: C.sub.25 H.sub.42 N.sub.2
O.sub.6 Si; Calc. C 60.70 H 8.56 N 5.66; Found C 60.59 H 8.76 N 5.49.
g1) Di-t-butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
cyclobut[cd]indene-2,6-dicarboxylate
Di-t-butyl
(1aS,3aR,6bR)-5-(t-butyl-dimethyl-silanyloxy-methyl)-1-oxo-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diazacyclo-but[cd]indene-2,6-dicarboxylate (5.61 g; 11.34
mmol) was dissolved in tetrahydrofuran (80 ml) and treated at room
temperature with 1N aqueous hydrochloric acid (23 ml). After 1 hour the
reaction mixture was diluted with ethyl acetate (200 ml) and washed in
succession with aqueous sodium bicarbonate solution (50 ml) and saturated
aqueous sodium chloride solution (50 ml), dried over magnesium sulphate
and concentrated. The residue was crystallized from n-hexane. Yield: 3.93
g (91%) as a colorless powder. M.p. 184.degree. C.
IR (KBr): 1761, 1705, 1631, 1253, 1161, 1117, 1087cm.sup.-1 ; MS (ISP):
(M+H).sup.+ 381.4.
EXAMPLE 2
Scheme 1, (1).fwdarw.(2),
Di-tert-butyl
(1aS,3aR,6bR)-5-Formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate
##STR27##
Di-tert-butyl
(1aS,3aR,6bR)-5-hydroxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
-cyclobut[cd]indene-2,6-dicarboxylate (Example 1) (1.14 g; 3 mmol) was
dissolved in methylene chloride (30 ml) and cooled to 0.degree. C. A
solution of KBr (56 mg; 0.47 mmol) and sodium bicarbonate (126 mg; 1.5
mmol) in dist. water (12 ml) was added in one portion. Then, a solution of
TEMPO (2,2,6,6-tetramethyl-piperidin-1-oxyl radical) (70 mg; 0.45 mmol) in
methylene chloride (3 ml) was added dropwise in about 5 minutes while
stirring well. Thereafter, 12 percent Javelle water (2.8 ml; 4.5 mmol) was
added dropwise and the mixture was subsequently stirred for a further 2
hours at 0.degree. C. The reaction mixture was poured into a separating
funnel and diluted with methylene chloride (100 ml) and 100 ml of a
saturated NaCl solution. The organic phase was separated and washed with
100 ml of a saturated NaCl solution. Both NaCl phases were back-extracted
with methylene chloride (100 ml), the combined organic phases were dried
over magnesium sulphate, suction filtered and concentrated. The product
obtained was dried to constant weight in a vacuum.
Yield: 1.13 g (100%) as an orange-red powder. IR (KBr): 2760, 1789, 1711,
1672, 1602, 1248, 1162 cm.sup.-1 ; MS (EI): 305 (M-tBuO.).
EXAMPLE 3
Scheme 1, Wittig Reaction (2).fwdarw.(3): Method A in the Presence of NaH
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-nitro-benzyl)-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarbo
xylate
##STR28##
(RS)-[2-Oxo-1-(4-nitro-benzyl)-pyrrolidin-3-yl]-triphenyl-phosphonium
bromide (202 mg; 0.36 mmol) was suspended in THF (3 ml), cooled to
0.degree. C and treated with sodium hydride (13 mg; 0.33 mmol).
Subsequently, the ice bath was removed and the mixture was stirred at room
temperature for a further 30 minutes. The reaction mixture was again
cooled to 0.degree. C. and treated with 114 mg (0.3 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) in ethylene chloride (9 ml).
After 30 minutes at 0.degree. C. the mixture was stirred for 24 hours at
room temperature. Thereafter, the reaction mixture was diluted with
methylene chloride (20 ml), the organic phase was separated and washed
with HCl 1N (10 ml) and twice with 10 ml of a saturated sodium chloride
solution, dried over magnesium sulphate, suction filtered and
concentrated. The residue obtained was chromatographed over silica gel (14
g, particle size 0.063-0.2 mm) with ethyl acetate.
Yield: 67 mg (39%) of a yellow, solid foam IR (KBr): 1775, 1701, 1 63S,
1522, 1346, 1246, 1661, 1030 cm.sup.-1 ; MS (ISP): 581.4 (M+H).sup.+ ;
598.4 (M+NH.sub.4).sup.+ ; 613.2 (M+H+CH.sub.3 OH).sup.+.
In analogy thereto there were prepared:
EXAMPLE 4
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-di
carboxylate
##STR29##
starting from 0.57 g (1.5 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut-[cd]indene-2,6-dicarboxylate (Example 2) and
(RS)-triphenyl-(1-thiophen-2-ylmethyl-2-oxo-pyrrolidin-3-yl)-phosphonium
bromide (0.94 g; 1.8 mmol).
Yield: 277 mg (35%) as a colorless powder. IR (KBr): 1773, 1698, 1633,
1244, 1160 cm.sup.-1 ; MS (ISP): 542.2 (M+H).sup.+.
EXAMPLE 5
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-1a
,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR30##
starting from 95 mg (0.25 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) and
(RS)-(1-isobutyl-2-oxo-pyrrolidin-3-yl)-triphenyl-phosphonium bromide (145
mg; 0.3 mmol).
Yield: 52 mg (42%) as a yellow resin IR (KBr): 1774, 1703, 1634, 1245, 1162
cm.sup.-1 ; MS (ISP): 502.3 (M+H).sup.+ ; 519.3 (M+NH.sub.4).sup.+.
EXAMPLE 6
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylat
e
##STR31##
starting from 570 mg (1.5 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) and
(RS)-(1-cyclopropyl-2-oxo-pyrrolidin-3-yl)-triphenyl-phosphonium bromide
840 mg; 1.8 mmol).
Yield: 690 mg (95%) as a yellow powder. IR (KBr): 1773, 1700, 1634, 1438,
1367, 1190 cm.sup.-1 ; MS (ISP): 486.4 (M+H).sup.+ ; 503.3
(M+NH.sub.4).sup.+.
EXAMPLE 7
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-phenyl-2-oxo-pyrrolidin-3-ylidenemethyl]-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR32##
starting from 95 mg (0.25 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) and
(RS)-(1-phenyl-2-oxo-pyrrolidin-3-yl)-triphenyl-phosphonium bromide (138
mg; 0.3 mmol).
Yield: 38 mg (29%) as a yellow powder. IR (KBr): 1778, 1689, 1632, 1 597,
1495, 760, 692 cm.sup.-1 ; MS (ISP): 522.2 (M+H).sup.+ ; 539.2
(M+NH.sub.4).sup.+ ; 544.2 (M+Na).sup.+.
EXAMPLE 8
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-2,6-dicarboxylate
##STR33##
starting from 95 mg (0.25 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) and
(RS)-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrrolidin-3-yl]-triphenyl
-phosphonium bromide (174 mg; 0.3 mmol).
Yield: 64 mg (43%) as a yellow powder. IR (KBr): 1775, 1699, 1636, 1246,
1161 cm.sup.-1 ; MS (ISP): 601.5 (M+H).sup.+ ; 618.5 (M+NH.sub.4).sup.+ ;
623.5 (M+Na).sup.+.
EXAMPLE 9
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxyla
te
##STR34##
starting from 855 mg (2.25 mmol) of di-tert-butyl (1aS,3aR,
6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-2,6-dicarboxylate (Example 2) and
(RS)-(2-oxo-1-pyridin-3-yl-pyrrolidin-3-yl)-triphenyl-phosphonium, bromide
(1.36 g; 2.7 mmol).
Yield: 352 mg (30%) as a yellow powder. IR (KBr): 1769, 1705, 1628, 1250,
1160 cm.sup.-1 ; MS (ISP): 523.2 (M+H).sup.+ ; 545.3 (M+Na).sup.+.
EXAMPLE 10
Scheme 1, Wittig reaction (2).fwdarw.(3): method B in the presence of LiOH.
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-tert-butoxycarbonyloxy-phenyl)-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-2,6-dicarboxylate
##STR35##
(RS)-[1-(4-tert-Butoxycarbonyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-
phosphonium bromide (340 mg; 0.55 mmol) and 190 mg (0.5 mmol) of
di-tert-butyl (1aS,3aR,
6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-2,6-dicarboxylate (Example 2) were suspended in methylene chloride (10
ml) and treated with molecular sieve 4 .ANG. (1 g) and lithium hydroxide
monohydrate (24 mg; 0.55 mmol). The mixture was stirred for 3 days at room
temperature. Then, the suspended material was removed by filtration and
the mother liquor was diluted with methylene chloride (about 100 ml),
washed with a mixture of 1N HCl (10 ml) and a saturated sodium chloride
solution (20 ml) and thereafter again washed with 2.times.30 ml of a
saturated sodium chloride solution. The aqueous phases were back-extracted
with methylene chloride (50 ml). The combined organic phases were dried
over magnesium sulphate, suction filtered and concentrated. The brown
residue was chromatographed over silica gel (60 g; particle size 0.063-0.2
mm) with ethyl acetate/hexane 2:1.
Yield: 44 mg (15%); IR (KBr): 1776, 1701, 1634, 1253, 1224, 1153 cm.sup.-1
; MS (ISP): 638.4 (M+H).sup.+ ; 655.4 (M+NH.sub.4).sup.+.
In analogy thereto there was prepared:
EXAMPLE 11
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(3-nitro-phenyl)-2-oxo-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarbo
xylate
##STR36##
starting from di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) (95 mg; 0.25 mmol) and
(RS)-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium-bromi
de (151 mg; 0.275 mmol) at 80.degree. C. in dichloroethane.
Yield: 47 mg (33%) as a yellow powder. IR (KBr): 1776, 1702, 1620, 1531,
1351 cm.sup.-1 ; MS (ISP): 584.3 (M+NH.sub.4).sup.+.
EXAMPLE 12
Scheme 1, Wittig reaction (2).fwdarw.(3): method C in the presence of
epoxybutane.
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-yl
idenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-
dicarboxylate
##STR37##
A suspension of di-tert-butyl
(1aS,3aR,6bR)-5-formyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-2,6-dicarboxylate (Example 2) (66 mg, 0.17 mmol) and
rac-[2-oxo-1-(2,2,2-trifluoro-ethyl)-3-pyrrolidinyl]-triphenylphosphonium
bromide (98 mg, 0.19 mmol, 1.1 eq.) in epoxybutane (8.5 ml) was heated
under reflux under Ar for 3.5 hours. The resulting reaction solution was
concentrated. The residue was taken up in methylene chloride (20 ml) and
washed with saturated sodium chloride solution (2.times.10 ml). The
aqueous phases were back-extracted with methylene chloride (20 ml). The
combined organic phases, dried over MgSO.sub.4, were concentrated and the
oily residue was chromatographed twice on silica gel (eluent methylene
chloride/acetone 19:1 and, respectively, tetrahydrofuran/hexane 2:3).
After crystallization from tert-butyl methyl ether there were obtained 29
mg (31%) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-d
icarboxylate as a white powder.
MS (ISP): 550.5 ((M+Na).sup.+, 10); 545.5 ((M+NH.sub.4).sup.+, 100); 528.4
((M+H).sup.+, 10). IR (KBr): 1773, 1705, 1634, 1265, 1159. Microanalysis:
C.sub.25 H.sub.32 N.sub.3 O.sub.6 F.sub.3 ; Calc. C 56.92, H 6.11, N 7.97,
F 10.80; Found. C 56.97, H 6.43, N 7.59, F 10.32.
Removal of the protecting group, scheme 1, (3).fwdarw.(4)
EXAMPLE 13
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyli
c acid trifluoroacetate (1:0.8)
##STR38##
A solution of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-tert-butoxycarbonyloxy-phenyl)-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-2,6-dicarboxylate (0.5 g; 0.784 mmol) (Example 10) in abs. methylene
chloride (2 ml) was added dropwise to abs. trifluoroacetic acid (8 ml) at
a temperature between (-20).degree. C. and (-18).degree. C. After 2 hours
at this temperature the solution was diluted with methylene chloride (14
ml) and stirred for a further 2 hours at room temperature. The reaction
mixture was concentrated. The residue was triturated with abs. ether (100
ml), filtered off under suction and washed with ether (2.times.20 ml). The
crystals were dried for 10 hours in a high vacuum.
Yield: 0.35 g (94%) as a yellow powder. IR (KBr): 2640, 1775, 1677, 1628,
1402, 1280, 1205, 836 cm.sup.-1 ; MS (ISP): 404.4 (M+Na).sup.+ ; 426.4
(M+2Na-H).sup.+.
In analogy thereto there were prepared:
EXAMPLE 14
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-car
boxylic acid trifluoroacetate (1:1)
##STR39##
Starting from di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-d
icarboxylate (Example 12) (160 mg, 0.30 mmol) there were obtained 121 mg
(0.25 mmol, 82%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-car
boxylic acid trifluoroacetate (1:1) as a beige precipitate.
MS (ISN): 370.3 ((M-H).sup.-, 100). IR (KBr): 1779, 1686, 1635, 1396, 1151
cm.sup.-1.
EXAMPLE 15
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-ylidenemeth
yl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.77)
##STR40##
Starting from 212 mg (0.365 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-nitro-benzyl)-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarbo
xylate (Example 3) there were obtained 158 mg (85%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.77) as a brownish powder.
IR (KBr): 1775, 1678, 1610, 1521, 1415, 1347, 1202 cm.sup.-1 ; MS (ISP):
425.2 (M+H).sup.+ ; 442.3 (M+NH.sub.4).sup.+.
EXAMPLE 16
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylide
nemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid trifluoroacetate (1:0.75)
##STR41##
Starting from 250 mg (0.472 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-di
carboxylate (Example 4) there were obtained 214 mg (96%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid trifluoroacetate (1:0.75) as a yellow powder.
IR (KBr): 2798, 1774, 1678, 1631, 1428, 1203 cm.sup.-1 ; MS (ISN): 383.9
(M-H).sup.- ; 401.1 (M+NH.sub.3 -H).
EXAMPLE 17
(E)-(1aS,3aR,6bR)-1-Oxo-5-[1-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-1
a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.7)
##STR42##
Starting from 250 mg (0.5 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-1a
,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]-indene-2,6-dicarboxylate
(Example 5) there were obtained 218 mg (88%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.7) as a brownish powder.
IR (KBr): 1775, 1677, 1632, 1202 cm.sup.-1 ; MS (ISP): 346.3 (M+H).sup.+.
EXAMPLE 18
(E)-(1aS,3aR,6bR)-1-Oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-ylidenemeth
yl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.7)
##STR43##
Starting from 460 mg (0.81 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(3-nitro-phenyl)-2-oxo-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarbo
xylate (Example 11) (460 mg; 0.81 mmol) there were obtained 280 mg (71%) of
(E)-(1aS,3aR,
6bR)-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-1a,2,3,3
a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.7) as a yellow powder.
IR (KBr): 1774, 1678, 1630, 1527, 1387, 1212 cm.sup.-1 ; MS (ISP): 411.3
(M+H).sup.+.
EXAMPLE 19
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.82)
##STR44##
Starting from 690 mg (1.4 mmo)l of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylat
e (Example 6) there were obtained 355 mg (59%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.82) as a beige powder.
IR (KBr): 1777, 1678, 1632, 1425, 1199 cm.sup.-1 ; MS (ISP): 330.3
(M+H).sup.+ ; 347.3 (M+NH.sub.4).sup.+ ; 352.3 (M+Na).sup.+.
EXAMPLE 20
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-1a,2,
3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.77)
##STR45##
Starting from 255 mg (0.49 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-phenyl-2-oxo-pyrrolidin-3-ylidenemethyl]-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]-indene-2,6-dicarboxylate
(Example 7) there were obtained 215 mg (97%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.77) as a beige powder.
IR (KBr): 3435, 2933, 1771, 1679, 1628, 1597, 1496, 1397, 1206 cm.sup.-1 ;
MS (ISP): 366.2 (M+H).sup.+ ; 388.2 (M+Na).sup.+.
EXAMPLE 21
(E)-(1aS,3aR,6bR)-1-Oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrrol
idin-3-ylidenemethyl]-1a,2,3,3a,4,
6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.73)
##STR46##
Starting from 418 mg (0.696 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-2,6-dicarboxylate (Example 8) there were obtained 310 mg (84%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-6-carboxylic acid trifluoroacetate (1:0.73) as a beige powder.
IR (KBr): 3433, 1773, 1685, 1630, 1279, 1206 cm.sup.-1 ; MS (ISP): 445.5
(M+H).sup.+ ; 462.4 (M+NH.sub.4).sup.+ ; 467.2 (M+Na).sup.+.
EXAMPLE 22
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:1.4)
##STR47##
Starting from 262 mg (0.5 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxyla
te (Example 9) there were obtained 263 mg (100%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:1,4) as a yellow powder.
IR (KBr): 1775, 1682, 1627, 1555, 1394, 1205 cm.sup.-1 ; MS (ISN): 365.2
(M-H).sup.-.
Acylation, Scheme 1, (4).fwdarw.(5)
EXAMPLE 23
(E)-(1aS,3aR,6bR)-2-(4-Carbamoyl-phenylcarbamoyl)-1-oxo-5-[2-oxo-1-(2,2,2-t
rifluoroethyl)-pyrrolidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a
-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt (1:1)
##STR48##
48 mg, 0.10 mmol of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:1) (Example 14) were placed in aceto-nitrile/water 1:1
(2 ml) and cooled to 0.degree. C. The solution was treated with sodium
bicarbonate (16 mg; 0.2 mmol) and 2,5-dioxo-pyrrolidin-1-yl
4-carbamoyl-phenylcarbamate (30 mg, 0.11 mmol). The mixture was stirred
for 10 minutes at 0.degree. C. Then, it was stirred for a further 1 to 2
hours at room temperature. The reaction mixture was subsequently diluted
with water (2 ml), washed with methylene chloride (3.times.3 ml) and
lyophilized. The residue was dissolved in a small amount of water and
chromatographed over a polymeric hydrophobic gel with water and
lyophilized. Yield: 34 mg (61%) as a yellowish lyophilizate.
MS (ISP): 556.4 ((M+H).sup.+, 45); 551.5 ((M-Na+H+NH.sub.4).sup.+, 70);
534.5 ((M-Na+2H).sup.+, 100). IR (KBr): 3429, 1753, 1663, 1605, 1525,
1389, 1152.
EXAMPLE 24
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3-
ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-
carboxylic acid sodium salt (1:1)
##STR49##
Acetyl chloride (59 .mu.l; 0.81 mmol) was added to a solution of 0.32 g;
0.675 mmol of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3-ylidenem
ethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyl
ic acid trifluoroacetate (1:0.8) (Example 13) and sodium hydrogen carbonate
(181 mg; 2.16 mmol) in DMF (8 ml) at (-10).degree. C. The reaction mixture
was stirred at (-10).degree. C. for 2.5 hours and then concentrated. The
residue was dissolved in a small amount of water and chromatographed over
a polymeric hydrophobic gel (eluent: water/acetonitrile). There were
obtained 113 mg (38%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3
-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6
-carboxylic acid sodium salt (1:1) as] a yellowish powder.
IR (KBr): 1752, 1621, 1393, 837 cm.sup.-1 ; MS (ISP): 468.2(M+H).sup.+.
In analogy thereto there were prepared:
EXAMPLE 25
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolid
in-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inde
ne-6-carboxylic acid sodium salt (1:1)
##STR50##
Starting from 80 mg (0.165 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-car
boxylic acid trifluoroacetate (1:1) (Example 14) and acetyl chloride (12
.mu.l, 0.165 mmol) there were obtained 29 mg (40%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrroli
din-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]ind
ene-6-carboxylic acid sodium salt (1:1) as a yellowish lyophilizate.
IR (KBr): 1756, 1690, 1623, 1395, 1151 cm.sup.-1 ; MS (ISN): 429.5
(M-Na+NH.sub.3).sup.- ; 412.4 (M-Na).sup.-.
EXAMPLE 26
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(4-nitro-benzyl)-pyrrolidin-3-y
lidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid sodium salt (1:1)
##STR51##
Starting from 122 mg (0.238 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.77) (Example 15) and acetyl chloride (21 .mu.l,
0.286 mmol) there were obtained 61 mg (53%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(4-nitrobenzyl)-pyrrolidin-3-y
lidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid sodium salt (1:1) as a reddish lyophilizate.
IR (KBr): 1752, 1626, 1520, 1394, 1345 cm.sup.-1. MS (ISP): 467.3
(M+H).sup.+ ; 484.2 (M+NH.sub.4).sup.+ ; 489.2 (M+Na).sup.+.
EXAMPLE 27
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidi
n-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inden
e-6-carboxylic acid sodium salt (1:1)
##STR52##
Starting from 80 mg (0.17 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid trifluoroacetate (1:0.75) (Example 16) and acetyl chloride (15
.mu.l, 0.204 mmol) there were obtained 50 mg (65%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolid
in-3-ylidenemethyl]-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1) as a yellow lyophilizate.
IR (KBr): 1753, 1624, 1395 cm.sup.-1. MS (ISP): 428.4 (M+H).sup.+ ; 445.4
(M+NH.sub.4).sup.+ ; 450.4 (M+Na).sup.+.
EXAMPLE 28
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-isobutyl-pyrrolidin-3-ylideneme
thyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyli
c acid sodium salt (1:1)
##STR53##
Starting from 142 mg (0.334 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(Isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.7) (Example 17) and acetyl chloride (30 .mu.l, 0.4
mmol) there were obtained 63 mg (46%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-isobutyl-pyrrolidin-3-ylidenem
ethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxyl
ic acid sodium salt (1:1) as a reddish lyophilizate.
IR (KBr): 1753, 1625, 1392 cm.sup.-1. MS (ISP): 388.2 (M+H).sup.+ ; 405.3
(M+NH.sub.4).sup.+ ; 410.3 (M+Na).sup.+.
EXAMPLE 29
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-yliden
emethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbox
ylic acid sodium salt (1:1)
##STR54##
Starting from 150 mg (0.355 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.82) (Example 19) and acetyl chloride (32 .mu.l,
0.426 mmol) there were obtained 49 mg (35%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylide
nemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid sodium salt (1:1) as an orange powder.
IR (KBr): 1754, 1624, 1392 cm.sup.-1. MS (ISP): 372.2 (M+H).sup.+ ; 389.2
(M+NH.sub.4).sup.+ ; 394.2 (M+Na).sup.+.
EXAMPLE 30
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-yl
idenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-ca
rboxylic acid sodium salt (1:1)
##STR55##
Starting from 130 mg (0.265 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.7) (Example 18) and acetyl chloride (24 .mu.l,
0.318 mmol) there were obtained 73 mg (58%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-(3-nitrophenyl)-2-oxo-pyrrolidin-3-y
lidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1756, 1680, 1617, 1528, 1390, 1347 cm.sup.-1. MS (ISN): 468.2
(M-Na+NH.sub.3).sup.-.
EXAMPLE 31
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemeth
yl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid sodium salt (1:1)
##STR56##
Starting from 91 mg (0.2 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-1a,2
,3, 3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.77) (Example 20) and acetyl chloride (18 .mu.l, 0.24
mmol) there were obtained 41 mg (48%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1751, 1670, 1622, 1600, 1391 cm.sup.-1. MS (ISP): 408.3
(M-Na+2H).sup.+ ; 425.5 (M-Na+H+NH.sub.4).sup.+ ; 430.4 (M+H).sup.+.
EXAMPLE 32
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-o
xo-pyrrolidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclo
but[cd]indene-6-carboxylic acid sodium salt (1:1)
##STR57##
Starting from 107 mg (0.2 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-oxo-pyrro
lidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]in
dene-6-carboxylic acid trifluoroacetate (1:0.73) (Example 21) and acetyl
chloride (18 .mu.l, 0.24 mmol) there were obtained 60 mg (59%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[1-(1-ethoxycarbonyl-piperidin-4-yl)-2-
oxo-pyrrolidin-3-ylidenemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cycl
obut[cd]indene-6-carboxylic acid sodium salt (1:1) as a red powder.
IR (KBr): 1756, 1690, 1625, 1600, 1386, 1212 cm.sup.-1. MS (ISP): 487.2
(M-Na+2H).sup.+ ; 504.2 (M-Na+H+NH.sub.4).sup.+ ; 509.1 (M+H).sup.+.
EXAMPLE 33
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylide
nemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid sodium salt (1:1)
##STR58##
Starting from 108 mg (0.2 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:1.4) (Example 22) and acetyl chloride (18 .mu.l,
0.24 mmol) there were obtained 58 mg (67%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1754, 1680, 1623, 1387 cm.sup.-1. MS (ISP): 409.3 (M+H).sup.+ ;
431.4 (M+Na).sup.+.
EXAMPLE 34
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(3-nitro-phenyl)-pyrrolidin-3-ylidenemet
hyl]-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]i
ndene-6-carboxylic acid sodium salt (1:1)
##STR59##
A solution of 135 mg (0.275 mmol)of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(3-nitrophenyl)-pyrrolidin-3-ylidenemet
hyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (Example 18) in DMF (3 ml) was treated with
concentrated trifluoroacetic acid (21 .mu.l; 0.275 mmol) and
dicyclohexylcarbodiimide (67 mg; 0.324 mmol) and stirred for 1hour at room
temperature. Subsequently, the reaction mixture was suction filtered, the
mother liquor was evaporated and the residue was treated with water (4
ml). The pH value was adjusted to 7.5 with a saturated sodium hydrogen
carbonate solution and the solution obtained was chromatographed over a
hydrophobic polymer.
Yield: 64 mg (44%) as a yellow powder. IR (KBr): 1764, 1691, 1614, 1529,
1483, 1390, 1347, 1214, 1151 cm.sup.-1 ; MS (ISN): 522.0
(M-Na+NH.sub.3).sup.-.
In analogy thereto there were prepared:
EXAMPLE 35
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-(thiophen-2-yl-methyl)-pyrrolidin-3-ylid
enemethyl]-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobu
t[cd]indene-6-carboxylic acid sodium salt (1:1)
##STR60##
Starting from 80 mg (0.17 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-ylmethyl)-pyrrolidin-3-ylid
enemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid trifluoroacetate (1:0.75) (Example 16) there were obtained 36
mg (42%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-(thiophen-2-yl-methyl)-pyrrolidin-3-yli
denemethyl]-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclob
ut[cd]indene-6-carboxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1763, 1691, 1618, 1393, 1366, 1153 cm.sup.-1 ; MS (ISP): 482.2
(M+H).sup.+ ; 504.1 (M+Na).sup.+.
EXAMPLE 36
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-cyclopropyl-pyrrolidin-3-ylidenemethyl]-
2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene
-6-carboxylic acid sodium salt (1:1)
##STR61##
Starting from 164 mg (0.387 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:0.82) (Example 19) there were obtained 72 mg
(42%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-cyclopropyl-pyrrolidin-3-ylidenemethyl]
-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inden
e-6-carboxylic acid sodium salt (1:1) as a beige powder.
IR (KBr): 1764, 1693, 1620, 1393, 1178, 1152 cm.sup.-1 ; MS (ISP): 426.4
(M+H).sup.+ ; 448.4 (M+Na).sup.+.
EXAMPLE 37
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-2-tri
fluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-ca
rboxylic acid sodium salt (1:1)
##STR62##
Starting from 86 mg (0.189 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid
trifluoroacetate (1:0.77) (Example 20) there were obtained 34 mg (38%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl]-2-tr
ifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-c
arboxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1760, 1690, 1616, 1600, 1391, 1180, 760, 700 cm.sup.-1 ; MS
(ISP): 462.3 (M-Na+2H).sup.+ ; 484.2 (M+H).sup.+.
EXAMPLE 38
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl]
-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inden
e-6-carboxylic acid sodium salt (1:1)
##STR63##
Starting from 108 mg (0.2 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid trifluoroacetate (1:1.4) (Example 22) there were obtained 52 mg (54%)
of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-oxo-1-pyridin-3-yl-pyrrolidin-3-ylidenemethyl
]-2-trifluoroacetyl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]inde
ne-6-carboxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1766, 1690, 1616, 1600, 1485, 1388, 1179 cm.sup.-1 ; MS (ISN):
478.1 (M+NH.sub.3 -Na).sup.-.
Quaternisation, Scheme 1, (5).fwdarw.(6)
EXAMPLE 39
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[1-(1-benzyl-pyridin-1-ium-3-yl)-2-oxo-pyrroli
din-3-ylidenemethyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[
cd]indene-6-carboxylate acid
##STR64##
75 mg (0.174 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(3-pyridinyl)-pyrrolidin-3-yli
denemethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-car
boxylic acid sodium salt (1:1) (Example 33) were dissolved in
dimethylformamide (1.5 ml) and treated with a 0.142 molar trifluoroacetic
acid solution in DMF (1.23 ml; 0.174 mmol). After stirring for 10 minutes
at room temperature benzyl bromide (41 .mu.l; 0.348 mmol) was added and
the mixture was subsequently stirred at room temperature for a further 21
hours. The reaction mixture was concentrated, the residue was taken up in
water (2 ml) and some acetonitrile and chromatographed over a hydrophobic
polymer with water/acetonitrile. There were obtained 54 mg (62%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[1-(1-benzyl-pyridin-1-ium-3-yl)-2-oxo-pyrrol
idin-3-ylidenemethyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut
[cd]indene-6-carboxylic acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1758, 1687, 1622, 1388 cm.sup.-1 ; MS (ISP): 499.4 (M+H).sup.+.
In analogy thereto there was prepared:
EXAMPLE 40
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[1-(1-carbamoylmethyl-pyridin-1-ium-3-yl)-2-ox
o-pyrrolidin-3-ylidenemethyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-
cyclobut[cd]indene-6-carboxylate
##STR65##
Starting from 75 mg (0.174 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(3-pyridinyl)-pyrrolidin-3-yli
dene-methyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]-indene-6-c
arboxylic acid sodium salt (1:1) (Example 33) and 2-bromo-acetamide (50 mg;
0.348 mmol) there were obtained 53 mg (66%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[1-(1-carbamoylmethyl-pyridin-1-ium-3-yl)-2-o
xo-pyrrolidin-3-ylidenemethyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza
-cyclobut[cd]indene-6-carboxylic acid sodium salt (1:1) as an orange
powder.
IR (KBr): 1757, 1694, 1624, 1390, 1215 cm.sup.-1 ; MS (ISP): 466.3
(M+H).sup.+.
EXAMPLE 41
Scheme 2, (1).fwdarw.(7)
Di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphoniummethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide
##STR66##
11.4 g (30 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-hydroxy-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaz
a-cyclobut[cd]indene-2,6-dicarboxylate were dissolved in methylene chloride
(100 ml), treated with molecular sieve 4 .ANG. (10 g) and cooled to
(-40).degree. C. The reaction mixture was treated with triethylamine (6.0
ml; 42 mmol) and methanesulphonyl chloride (3.3 ml; 42 mmol), with the
temperature rising to (-14).degree. C. As soon as the temperature has
again fallen to (-40.degree. C., a solution of calcium iodide (10.98 g; 30
mmol) in dimethyl sulphoxide (300 ml) was added in one portion, with the
temperature rising to +10.degree. C. The reaction mixture was cooled to
0.degree. C. and stirred for a further hour. Subsequently, the solution
was poured into 500 ml of ice-cold 1 N HCl and extracted with ethyl
acetate (2.times.700 ml). The combined organic phases were washed in
succession with 5% sodium thiosulphate solution (250 ml and 100 ml),
saturated sodium hydrogen sulphate solution (100 ml) and saturated sodium
chloride solution (2.times.100 ml), dried over magnesium sulphate, suction
filtered and concentrated. The white residue obtained was triturated
briefly with pentane (150 ml), filtered off under suction and dried to
constant weight in a high vacuum. The white powder obtained (8.95 g) was
taken up immediately in DMSO (90 ml) and acetonitrile (90 ml), treated
with triphenylphosphine (9.55 g; 36.5 mmol) and stirred for 20 hours at
50.degree. C. The reaction mixture was cooled to room temperature and
extracted with water (300 ml) and ether (500 ml). The separated aqueous
phase was back-washed with ether (300 ml). The two organic phases were
back-extracted with water (100 ml). The combined aqueous phases were
extracted with methylene chloride (2.times.300 ml) after saturation with
NaCl. The methylene chloride phases were subsequently washed with a
saturated sodium chloride solution (300 ml), dried over magnesium sulphate
suction filtered and concentrated. The colorless resin obtained was
triturated with ether (500 ml), filtered off under suction and dried to
constant weight in a high vacuum. There were obtained 13.45 g (98%) of
di-tert-butyl (1aS,3aR,6bR)-5-triphenylphosphoniummethyl-1-oxo-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide
as a white powder.
IR (KBr): 1773, 1699, 1621, 1590, 1439, 1164, 1111 cm.sup.-1 ; MS (ISP):
625.4 (M.sup.+).
Wittig Reaction, Scheme 2, (7).fwdarw.(8)
EXAMPLE 42
Di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-3-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]Indene-2,6-dicarboxylate
##STR67##
2.41 g (3.2 mmol) of di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphoniummethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 41) were
dissolved in 80 ml of abs. dimethyl sulphoxide and treated with
pyridine-3-aldehyde (0.62 ml; 6.4 mmol) and triethylamine (1.12 ml; 8.0
mmol). After 24 hours at room temperature the reaction mixture was poured
into 400 ml of phosphate buffer solution (pH 7) and extracted with ethyl
acetate (2.times.200 ml). The combined organic 30 phases were subsequently
washed with water (2.times.100 ml) and saturated sodium chloride solution
(100 ml), dried over magnesium sulphate, suction filtered and
concentrated. The residue obtained was chromatographed over silica gel
(275 g; particle size 0.063-0.2 mm) with ethyl acetate/hexane 1:1. There
were obtained 1.42 g (98%) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-3-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate as a yellow powder.
IR (KBr): 1769, 1704, 1634, 1162 cm.sup.-1 ; MS (ISP): 454.5 (M+H).sup.+.
In analogy thereto there were prepared:
EXAMPLE 43
Di-tert-butyl
(E)-(1aS,3aR,6bR)-5-styryl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cy
clobut[cd]indene-2,6-dicarboxylate
##STR68##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (151 mg; 0.2
mmol) (Example 41) and benzaldehyde (40 .mu.l; 0.4 mmol).
Yield: 81 mg (90%) as a colorless powder. IR (KBr): 1764, 1704, 1580, 1478,
1250, 970 cm.sup.-1 ; MS (ISP): 453.5 (M+H).sup.+.
EXAMPLE 44
Di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-2-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR69##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (2.41 g; 3.2
mmol) (Example 41) and pyridine-2-carboxaldehyde (0.63 ml; 6.4 mmol).
Yield: 1.13 g (78%) as a colorless powder. IR (KBr): 1774, 1706, 1622,
1581, 1243, 1161 cm.sup.-1 ; MS (ISP): 454.5 (M+H).sup.+.
EXAMPLE 45
Di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-4-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR70##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (2.41 g; 3.2
mmol) (Example 41) and pyridine-4-carboxaldehyde (0.63 ml; 6.4 mmol).
Yield: 1.20 g (80%) as a colorless powder. IR (KBr): 1773, 1705, 1594,
1439, 1161 cm.sup.-1 ; MS (ISP): 454.5 (M+H).sup.+.
EXAMPLE 46
Di-tert-butyl
(E)-(1aS,3aR,6bR)-5-[2-(4-tert-butoxy-carbonyloxy-phenyl)-vinyl]-1-oxo-1a,
2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR71##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (1.2 g; 1.6
mmol) (Example 41) and carboxylic acid tert-butyl ester 4-formyl-phenyl
ester (711 mg; 3.2 mmol).
Yield: 0.6 g (66%) as a colorless powder. IR (KBr): 1762, 1706, 1507, 1254,
1153 cm.sup.-1 ; MS (ISP): 569.5 (M+H).sup.+.
EXAMPLE 47
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR72##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (2.41 g; 3.2
mmol) (Example 41) and quinoline-2-carbaldehyde (1.0; 6.4 mmol).
Yield: 1.5 g (94%) as a yellow foam-like resin. IR (KBr): 1775, 1706, 1246,
1160 cm.sup.-1 ; MS (ISP): 504.5 (M+H).sup.+.
EXAMPLE 48
Di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
##STR73##
From di-tert-butyl
(1aS,3aR,6bR)-5-triphenylphosphonium-methyl-1-oxo-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate bromide (2.41 g; 3.2
mmol) (Example 41) and quinoline-3-carbaldehyde (1.0; 6.4 mmol). Yield:
1.5 g (94%) as a yellow powder.
IR (KBr): 1770, 1705, 1621, 1476, 1161, 946 cm.sup.-1 ; MS (ISP): 504.4
(M+H).sup.+.
Removal of the protecting group, Scheme 2, (8).fwdarw.(9)
The following Examples were performed analogously to Example 13 (Scheme 1
(3).fwdarw.(4)):
EXAMPLE 49
(E)-(1aS,3aR,6bR)-1-Oxo-5-styryl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyc
lobut[cd]indene-6-carboxylic acid trifluoroacetate
##STR74##
Starting from 100 mg (0.22 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-styryl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cy
clobut[cd]indene-2,6-dicarboxylate (Example 43) there were obtained 83 mg
(98%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-styryl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cy
clobut[cd]indene-6-carboxylic acid trifluoroacetate as a colorless powder.
IR (KBr): 3432, 1773, 1678, 1619, 1200, 966, 750, 693 cm.sup.-1 ; MS (ISN):
295.3 (M-H).sup.-.
EXAMPLE 50
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-1
H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.58)
##STR75##
Starting from 303 mg (0.668 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-2-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 44) there were
obtained 300 mg (94%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.58) as an orange powder.
IR (KBr): 1780, 1678, 1633, 1576, 1410, 1201 cm.sup.-1 ; MS (ISP): 298.2
(M+H).sup.+.
EXAMPLE 51
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-1
H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.45)
##STR76##
Starting from 363 mg (0.8 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-4-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 45) there were
obtained 203 mg (55%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.45) as an orange powder.
IR (KBr): 1775, 1679, 1638,1 613, 1198 cm.sup.-1 ; MS (ISP): 298.3
(M+H).sup.+.
EXAMPLE 52
(E)-(1aS,3aR,6bR)-1-Oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,4,6b-hexah
ydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:0.83)
##STR77##
Starting from 571 mg (1mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-[2-(4-tert-butoxycarbonyloxy-phenyl)-vinyl]-1-oxo-1a,2
,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate
(Example 46) there were obtained 375 mg (92%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,4,6b-hexa
hydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:0.83) as a yellow powder.
IR (KBr): 1769, 1677, 1602, 1512, 1200 cm.sup.-1 ; MS (ISN): 311.3
(M-H).sup.-.
EXAMPLE 53
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-1
H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.5)
##STR78##
Starting from 1.42 g (3.13 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-5-(2-pyridin-3-yl-vinyl)-1-oxo-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 42) there were
obtained 1.05 g (72%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.5)
as a yellow powder.
IR (KBr): 1773, 1679, 1631, 1202, 970 cm.sup.-1 ; MS (ISP): 279.4
(M+H).sup.+ ; 298.4 (M+NH.sub.4).sup.+ ; 301.3 (M+Na).sup.+.
EXAMPLE 54
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.5)
##STR79##
Starting from 1.5 g (2.97 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 47) there were
obtained 1.3 g (86%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.5) as a dark red powder.
IR (KBr): 1772, 1677, 1644, 1619, 1204, 960, 725 cm.sup.-1 ; MS (ISP):
348.4 (M+H).sup.+ ; 366.4 (M+NH.sub.4).sup.+ ; 370.3 (M+Na).sup.+.
EXAMPLE 55
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.4)
##STR80##
Starting from 1.5 g; (3 mmol) of di-tert-butyl
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-2,6-dicarboxylate (Example 48) there were
obtained 1.25 g (82%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.4) as an orange powder.
IR (KBr): 1771, 1679, 1633, 1203, 970, 722 cm.sup.-1 ; MS (ISP): 348.2
(M+H).sup.+.
Acylation, Scheme 1, (9).fwdarw.(10)
EXAMPLE 56
(E)-(1aS,3aR,6bR)-2-Formyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR81##
198 mg (0.4 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.58) (Example 50) were dissolved in 4 ml of dimethylformamide, cooled
to 0.degree. C. and treated with concentrated formic acid (0.3 ml; 8 mmol)
and dicyclohexylcarbodiimide (181 mg; 0.88 mmol). After 2 hours at
0.degree. C. the precipitated material was filtered off under suction and
the mother liquor was concentrated. The residue was suspended in 5 ml of
water and the pH was adjusted to 7.5 with a saturated sodium hydrogen
carbonate solution. The dissolved material was chromatographed over a
hydrophobic polymer with water/acetonitrile 4:1. There were obtained 82 mg
(59%) of
(E)-(1aS,3aR,6bR)-2-formyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as a red powder.
IR (KBr): 1754, 1659, 1602, 1390, 975, 769 cm.sup.-1 ; MS (ISP): 326.3
(M+2H-Na).sup.+ ; 348.3 (M+H).sup.+.
The following Examples were performed in analogy to Example 24 (Scheme 1
(4).fwdarw.(5)):
EXAMPLE 57
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-styryl-1a,2,3,3a,4,
6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1)
##STR82##
Starting from 65 mg (0.168 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-styryl-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cy
clobut[cd]indene-6-carboxylic acid trifluoroacetate (Example 49) and acetyl
chloride (15 .mu.l; 0.2 mmol) there were obtained 27 mg (45%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-styryl-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt(1:1) as a colorless powder.
IR (KBr): 1748, 1619, 1605, 1394, 970, 751, 695 cm.sup.-1 ; MS (ISP): 339.2
(M+H).sup.+ ; 356.3 (M+NH.sub.4).sup.+ ; 361.2 (M+Na).sup.+.
EXAMPLE 58
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR83##
Starting from 141 mg (0.295 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.58) (Example 50) and acetyl chloride (26 .mu.l; 0.354 mmol) there
were obtained 38 mg (36%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as a colorless powder.
IR (KBr): 1751, 1650, 1621, 1390, 770 cm.sup.-1 ; MS (ISP): 340.3
(M-Na+2H).sup.+ ; 362.3 (M+H).sup.+ ; 384.2 (M+Na).sup.+.
EXAMPLE 59
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR84##
Starting from 155 mg (0.236 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.45) (Example 51) and acetyl chloride (30 .mu.l; 0.4 mmol) there were
obtained 76 mg (62%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-4-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as a red powder.
IR (KBr): 1752, 1670, 1600, 1389 cm.sup.-1 ; MS (ISP): 340.3 (M+H).sup.+ ;
358.3 (M+NH.sub.4).sup.+ ; 362.3 (M+Na).sup.+.
EXAMPLE 60
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,4
,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1)
##STR85##
Starting from 122 mg (0.3 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,4,6b-hexa
hydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:0.83) (Example 52) and acetyl chloride (27 .mu.l; 0.36 mmol) there were
obtained 82 mg (72%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-(4-hydroxy-phenyl)-vinyl]-1a,2,3,3a,
4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1) as a yellow powder.
IR (KBr): 1744, 1640, 1604, 1511, 1447, 1245, 1170, 1013, 968 cm.sup.-1 ;
MS (ISP): 355.3 (M-Na+2H).sup.+ ; 372.3 (M-Na+H+NH.sub.4).sup.+ ; 377.2
(M+H).sup.+.
EXAMPLE 61
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR86##
Starting from 1.3 g (2.55 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.5) (Example 54) and acetyl chloride (225 .mu.l; 3.06 mmol) there were
obtained 231 mg (22%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diaza-cycIobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as a red powder.
IR (KBr): 1750, 1611, 1453, 970, 750 cm.sup.-1 ; MS (ISP): 390.4
(M-Na+2H).sup.+ ; 412.2 (M+H).sup.+.
EXAMPLE 62
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-he
xahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR87##
Starting from 1.03 g (2.2 mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate (1:1.5)
(Example 53) and acetyl chloride (194 .mu.l; 2.64 mmol) there were
obtained 434 mg (55%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as an orange powder.
IR (KBr): 1749, 1650, 1622, 1418, 1392, 1361, 968 cm.sup.-1 ; MS (ISP):
340.4 (M-Na+2H).sup.+ ; 362.3 (M+H).sup.+.
EXAMPLE 63
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1)
##STR88##
Starting from 507 mg (1mmol) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro
-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.4) (Example 55) and acetyl chloride (88 .mu.l; 1.2 mmol) there were
obtained 234 mg (57%) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-quinolin-3-yl-vinyl)-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) as a yellow powder.
IR (KBr): 1749, 1660, 1621, 1490, 1393, 960, 754 cm.sup.-1 ; MS (ISP):
390.4 (M+H).sup.+ ; 412.3 (M+Na).sup.+.
The following Example was performed analogously to Example 34 (Scheme 1,
(4).fwdarw.(5)):
EXAMPLE 64
(E)-(1aS,3aR,6bR)-1-Oxo-5-(2-pyridin-2-yl-vinyl)-2-trifluoroacetyl-1a,2,3,3
a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1)
##STR89##
Starting from 141 mg () of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-hexahydro-
1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid trifluoroacetate
(1:1.58) (Example 50) there were obtained 51 mg (42%) of
(E)-(1aS,3aR,6bR)-1-oxo-5-(2-pyridin-2-yl-vinyl)-2-trifluoroacetyl-1a,2,3,
3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium
salt (1:1) as an orange powder.
IR (KBr): 1761, 1693, 1622, 1393, 1154 cm.sup.-1 ; MS (ISP): 394.2
(M+2H-Na).sup.+ ; 416.3 (M+H).sup.+.
Quaternisation, Scheme 2, (10).fwdarw.(11)
The following Examples were performed analogously to Example 39, (Scheme 1,
(5).fwdarw.(6)):
EXAMPLE 65
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-benzyl-pyridin-1-ium-2-yl)-vinyl]-1-oxo-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylate
##STR90##
Starting from 75 mg (0.207 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(Example 58) there were obtained 41 mg (47%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[2-(1-benzyl-pyridin-1-ium-2-yl)-vinyl]-1-oxo
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid sodium salt (1:1) as a yellow powder.
IR (KBr): 1769, 1714, 1645, 1429, 970, 740, 700 cm.sup.-1 ; MS (ISP): 430.5
(M+H).sup.+.
EXAMPLE 66
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-benzyl-pyridin-1-ium-3-yl)-vinyl]-1-oxo-
1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylate
##STR91##
Starting from 75 mg (0.207 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(Example 62) there were obtained 65 mg (74%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[2-(1-benzyl-pyridin-1-ium-3-yl)-vinyl]-1-oxo
-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic
acid sodium salt (1:1) as an orange powder.
IR (KBr): 1768, 1710, 1643 cm.sup.-1 ; MS (ISP): 430.5 M.sup.+.
The following Examples were performed analogously to Example 40 (Scheme 1,
(5).fwdarw.(6)):
EXAMPLE 67
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-carbamoylmethyl-pyridin-1-ium-3-yl)-viny
l]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbox
ylate
##STR92##
Starting from 75 mg (0.207 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]-indene-6-carboxylic acid sodium salt
(1:1) (Example 62) there were obtained 39 mg (39%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[2-(1-carbamoylmethyl-pyridin-1-ium-3-yl)-vin
yl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid sodium salt (1:1) as an orange powder.
IR (KBr): 1754, 1695, 1618, 1505, 1207, 970 cm.sup.-1 ; MS (ISP): 397.4
M.sup.+.
EXAMPLE 68
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-carbamoylmethyl-quinolin-1-ium-3-yl)-vin
yl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylate
##STR93##
Starting from 82 mg (0.2 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-quinolin-2-yl-vinyl)-1a,2,3,3a,4,6b-
hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) (Example 63) there were obtained 20 mg (22%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[2-(1-carbamoylmethyl-quinolin-1-ium-3-yl)-vi
nyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carb
oxylic acid sodium salt (1:1) as a brown powder.
IR (KBr): 1754, 1696, 1621, 1530, 1389, 780 cm.sup.-1 ; MS (ISP): 447.5
(M+H).sup.+.
EXAMPLE 69
(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[(E)-2-[1-[(E)-3-phenylallyl]-pyridin-1-ium-
3-yl)-vinyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-ca
rboxylate
##STR94##
Analogously to Example 39, starting from 55 mg (0.152 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) (Example 62) and 3-bromo-1-phenyl-1-propene (61 mg; 0.304 mmol).
Yield: 44 mg (64%) as an orange powder. IR (KBr): 1754, 1621, 1400, 970
cm.sup.-1 ; MS (ISP) 456.4 (M+H).sup.+.
EXAMPLE 70
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-[1-[(4-hydroxyphenylcarbamoyl)-methyl]-pyri
din-1-ium-3-yl)-vinyl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobu
t[cd]indene-6-carboxylate
##STR95##
Analogously to Example 39, starting from 55 mg (0.152 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) (Example 62) and 2-bromo-4'-hydroxyacetanilide (70 mg; 0.304 mmol).
Yield: 42 mg (57%) as an orange powder.
IR (KBr): 1754, 1683, 1625, 1577, 1513, 1392, 1363, 1252 cm.sup.-1 ; MS
(ISP): 489.2 (M+H).sup.+.
EXAMPLE 71
(E)-(1aS,3aR,6bR)-2-Acetyl-1-oxo-5-[2-[1-[(4-trifluoromethoxy-benzyl)-pyrid
in-1-ium-3-yl]-vinyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]in
dene-6-carboxylate
##STR96##
Analogously to Example 39, starting from 55 mg (0.1 52 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-3-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) (Example 62) and 4-trifluoromethoxy-benzyl bromide (78 mg; 0.304
mmol).
Yield: 40 mg (51%) as an orange powder. IR (KBr): 1756, 1619, 1507, 1421,
1389, 1362, 1315, 1259, 1217, 1166, 960 cm.sup.-1 ; MS (ISP): 514.3
(M+H).sup.+.
EXAMPLE 72
(E)-(1aS,3aR,6bR)-2-Acetyl-5-[2-(1-carbamoylmethyl-pyridin-1-ium-2-yl)-viny
l]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbox
ylate
##STR97##
Starting from 50 mg (0.138 mmol) of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-(2-pyridin-2-yl-vinyl)-1a,2,3,3a,4,6b-h
exahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carboxylic acid sodium salt
(1:1) (Example 58) there were obtained 26 mg (37%) of
(E)-(1aS,3aR,6bR)-2-acetyl-5-[2-(1-carbamoylmethyl-pyridin-1-ium-2-yl)-vin
yl]-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-carbo
xylic acid sodium salt (1:1) as an orange powder.
IR (KBr): 1753, 1677, 1621, 980 cm.sup.-1 ; MS (ISP): 397.4 M.sup.+.
EXAMPLE 73
Production of dry ampoules for intramuscular administration:
A lyophilizate of 0.5 g of
(E)-(1aS,3aR,6bR)-2-acetyl-1-oxo-5-[2-oxo-1-(4-hydroxyphenyl)-pyrrolidin-3
-ylidenmethyl]-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diaza-cyclobut[cd]indene-6-
carboxylic acid sodium salt (Example 24) and 1 g of ceftriaxone is prepared
and filled into an ampoule. Prior to administration the lyophilizate is
treated with 4 ml of a 2% aqueous lidocaine hydrochloride solution.
If desired, the two active substances can be filled separately into two
different ampoules.
A different compound of formula I can also be used as the active substance.
In addition to ceftriaxone, other known .beta.-lactam antibiotics come
into consideration as the .beta.-lactam antibiotic.
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